Gastric retentive extended-release dosage forms comprising combinations of a non-opioid analgesic and an opioid analgesic

ABSTRACT

Compositions and methods for the treatment of pain in a mammal are described. More specifically, a dosage form designed for release of acetaminophen and an opioid is described, wherein the dosage form provides delivery of the drugs to the upper gastrointestinal tract (“GI”) of a mammal for an extended period of time.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/196,143, filed Mar. 4, 2014, which is a continuation of U.S.application Ser. No. 13/529,960, filed Jun. 21, 2012, now U.S. Pat. No.8,668,929, which is a continuation of U.S. application Ser. No.12/644,444, filed Dec. 22, 2009, now U.S. Pat. No. 8,372,432, issuedFeb. 12, 2013, which is a continuation-in-part of U.S. application Ser.No. 12/402,477, filed Mar. 11, 2009, now U.S. Pat. No. 8,377,453, issuedFeb. 19, 2013, which claims the benefit of U.S. Provisional ApplicationSer. No. 61/035,696, filed Mar. 11, 2008, all of which are incorporatedherein by reference in their entirety.

TECHNICAL FIELD

Compositions and methods are described for relief or treatment ofexisting or anticipated pain. In some embodiments, gastric retentive(“GR®”) dosage forms comprise acetaminophen (APAP) in combination withan opioid analgesic and are administered to a person suffering from,diagnosed with or at risk of experiencing pain. The dosage forms whenadministered to a mammal, typically provide about 3 hours to about 12hours of delivery of one or both of the drugs to the uppergastrointestinal (“GI”) of the mammal. The present disclosure alsorelates to a method for treating pain by providing the gastric retentivedosage forms, and to methods of making the gastric retentive dosageforms.

BACKGROUND

It is often desirable to administer to a mammalian subject an opioidanalgesic combined with a non-opioid analgesic agent, for example,acetaminophen (APAP). Such combination formulations provide theadvantage of additive analgesic effects with a lower dose of opioid, andhence a resulting lower incidence of side effects and the ability totreat a broader spectrum of pain or pain states due to differentmechanisms of actions.

Such is the case for combinations of acetaminophen or aspirin withopioids, such as oxycodone (Percocet® and Percodan®, respectively), orhydrocodone (Vicodin® and Lortab®, respectively) or acetaminophen withcodeine (Tylenol® with codeine). However, these currently marketed drugproducts deliver the combination drugs as an immediate release product.Accordingly, the drug product has to be administered quite frequentlyand at least every 4 to 6. Currently, extended-release oral dosage formsfor delivery of the above active ingredients are only available fordelivery of a single active pharmaceutical ingredient. For example,Tylenol® Extended Release for Arthritis provides a dosage of 650milligrams acetaminophen to be administered every 8 hours. OxyContin® isformulated to provide controlled release of oxycodone hydrochloride viatwice-daily administration.

When treating a mammalian subject suffering from or diagnosed with achronic or acute pain state, it is highly desirable to maintain andachieve analgesia continuously. Immediate release formulations of theappropriate therapeutic agents require frequent and/or continuous dosingthroughout the day (or night) for continuous pain relief. This is ofteninconvenient and difficult to maintain regularly dosing and frequentlyleads to poor patient compliance, potentially resulting in a dose beingtaken after pain breaks through again, causing unnecessary pain andsuffering.

Hence, it would be desirable and beneficial to provide extended releasedelivery of a drug product that comprises both an opioid and anon-opioid analgesic such as acetaminophen. Such a dosage form wouldreduce the frequency of administration to a subject while sustainingplasma drug levels and analgesic effects throughout the day (or night).Such an extended release dosage form would eliminate the need to dosefrequently to maintain analgesia, which is often inconvenient anddifficult to maintain regularly, with the result that the next dose istaken after the pain breaks through again, causing unnecessary pain andsuffering. Additionally, such a dosage form would increase patientcompliance while minimizing adverse effects or events.

Gastric retentive dosage forms have demonstrated success in providingextended delivery of active ingredients. Drugs that are delivered from agastric retained dosage form continuously bathe the stomach, duodenumand upper part of the small intestine for many hours. Release of thedrug from the dosage form upstream of absorption sites provides extendedand controlled exposure of the absorption sites to the released drug,thus increasing bioavailability. Acetaminophen demonstrates reducedbioavailability when administered rectally (about 35-50%) as compared tooral administration (about 60-70%). The increasingly dry environment ofthe colon is unfavorable for absorption. Accordingly, a gastricretentive extended release dosage form would provide several significantadvantages as it would obviate the bioavailability reduction seen in thecolon with non-gastric retentive extended release dosage forms.

Although gastric retentive dosage forms containing a drug dispersed in aswellable polymer matrix have been previously described, new challengesarise when formulating dosage forms that can provide the therapeuticallyeffective delivery of a combination of drugs, which include, forexample, acetaminophen and an opioid. Firstly, these two active agentshave very different solubilities. Acetaminophen is a sparingly solubledrug in water, having a solubility of about 1-5 milligrams/milliliter(mg/ml) in water at 22° C. In contrast, opioids, which are formulated asacid salts in drug products, are highly soluble in water. For example,oxycodone HCl (100 to 167 (mg/ml), hydrocodone bitartrate (62.5 mg/ml),and codeine phosphate (400 to 435 mg/ml). Such disparities in solubilityshould be taken into account when formulating a dosage form thatreleases the two active agents at rates proportional to each other.Secondly, opioids are known to inhibit gastric motility. Such inhibitioncan negatively impact the erosion rate of a gastric retentive dosageform as needed for the desired drug release profile. Finally,acetaminophen is known to be difficult for the production of solid oraldosage forms. It can be particularly difficult to produce a tablethaving acetaminophen because acetaminophen powder does not compresseasily to form a stable tablet. Moreover, preparation of tablets havingnecessary dosage levels requires a relatively high weight percent of thedrug. As a result, production of a useful tablet size allows only lowamounts of excipients. This contributes to the difficulties involved inproducing a tablet that relies on the use of a swellable polymer forextended release.

The present disclosure meets these challenges and needs, among others.

SUMMARY

The present disclosure provides, among other aspects, gastric retentivedosage forms for oral administration to a subject, such as a humanpatient, for relief from a pain state. The dosage form in someembodiments is a gastric retentive dosage form that contains a firstdose of at least one drug as an extended release (“ER”) portion, and asecond dose of at least one drug as an immediate release (“IR”)component. The dosage forms typically contain a therapeuticallyeffective amount of acetaminophen (APAP) and a therapeutically effectiveamount of an opioid or opioid-like analgesic.

In one aspect, the ER portion of the dosage form comprises an opioid andacetaminophen containing a first dose of the opioid and a first dose ofacetaminophen. In another aspect, the ER portion of the dosage formcomprises the first dose of opioid and the first dose of acetaminophendispersed in a polymer matrix comprising at least one hydrophilicpolymer. Upon administration, the polymer matrix is able to swell uponimbibition of fluid to a size sufficient such that the ER portion of thedosage form is retained in a stomach of a subject in a fed mode and thefirst dose of opioid and the first dose of acetaminophen are releasedover an extended period of time. The ER portion may alternatively bereferred to herein as the gastric retentive or “GR” portion.

In another aspect, the dosage form releases the acetaminophen througherosion of the polymer matrix and the opioid is released at a rateproportional to the release of the acetaminophen. In another embodiment,the dosage form releases the acetaminophen through both erosion anddiffusion. In additional embodiments, the rate of release of the opioidis about 2% to about 10%, or about 4% to about 8%, or about 5% or about7% of the rate of release of the acetaminophen, over a period of releasefrom between about 2 to about 10 hours, or about 4 to about 6 hours, orabout 4 to about 8 hours.

In one embodiment, the opioid or opioid-like analgesic is tramadol,hydrocodone, oxycodone, hydromorphone or codeine.

In one embodiment, the ER portion of the dosage form comprises a firstdose of acetaminophen of about 100 milligrams (mg) to about 600 mg andis delivered over an extended period of time. In another embodiment, thefirst dose of acetaminophen is about 200 mg to about 400 mg, or about275 mg to about 325 mg. In yet another embodiment, the first dose ofacetaminophen is about 270 mg, 275 mg, 280 mg, 285 mg, 290 mg, 295 mg,300 mg, 304 mg, 305 mg, 310 mg, 315 mg, 320 mg, 325 mg or 330 mg. Inanother aspect, the ER portion of the dosage form comprises a first doseof acetaminophen that is approximately 25 weight percent (wt %), 30 wt%, 35 wt %, 38 wt %, 39 wt %, 40 wt %, 41 wt %, 42 wt %, 43 wt %, 44 wt%, 45 wt %, 47 wt %, 50 wt %, 55 wt %, 60 wt %, 65 wt % or 70 wt % ofthe total weight of the dosage form.

In one embodiment, the ER portion of the dosage form comprises a firstdose of opioid of about 10 mg to about 100 mg. In another embodiment,the first dose of opioid is about 14 mg to about 25 mg. In anotherembodiment, the first dose of opioid is about 15 mg to about 50 mg. Inan additional embodiment, the first dose of opioid is about 16 mg toabout 30 mg. In another embodiment, the first dose of opioid is about16.5 mg to about 20 mg. In yet another embodiment, the first dose ofopioid is about 15.0 mg, 15.5 mg, 16.0 mg, 16.5 mg, 17.0 mg, 17.5 mg,18.0 mg, 18.5 mg, 19.0 mg, 19.5 mg, or 20.0 mg. In yet anotherembodiment, the ER portion of the polymer matrix comprises a first doseof opioid that is approximately 1.0 wt %, 1.5 wt %, 2.0 wt %, 2.2 wt %,2.5 wt %, 2.6 wt %, 2.7 wt %, 2.8 wt %, 3.0 wt %, 3.2 wt %, 3.5 wt %,4.0 wt %, 4.5 wt %, 5.0 wt %, 5.5 wt %, 6.0 wt %, 6.5 wt %, 7.0 wt %,7.5 wt %, 8.0 wt %, 8.5 wt %, 9.0 wt %, 9.5 wt % or 10 wt % of the totalweightt of the ER portion of the dosage form.

In another embodiment, the weight percent of acetaminophen is typicallybetween about 10 to 20 times, more typically between 14 to 17 times theweight percent of opioid in the ER portion of the dosage form.

In one embodiment, the at least one polymer is a polyalkylene oxide. Inanother aspect, the polyalkylene oxide is poly(ethylene) oxide. In afurther embodiment, the poly(ethylene) oxide has an approximatemolecular weight between 500,000 Daltons (Da) to about 10,000,000 Da orabout 900,000 Da to about 7,000,000 Da. In yet a further embodiment, thepoly(ethylene) oxide has a molecular weight of approximately 600,000 Da,900,000 Da, 1,000,000 Da, 2,000,000 Da, 4,000,000 Da, 5,000,000 Da,7,000,000 Da, 9,000,000 Da and 10,000,000 Da.

In another embodiment, the polymer is present in the ER portion of thedosage form from about 15 wt % to about 70 wt %, or about 20 wt % toabout 60 wt %, or about 25 wt % to about 55 wt % of the total wt % ofthe dosage form of the ER portion. In another embodiment, the polymer ispresent in the ER portion of the dosage form in an amount ranging fromabout 30 wt % to about 50%, or about 35 wt % to about 45 wt %. In yetanother embodiment, the polymer is present in the ER portion of thedosage form in an amount equal to approximately 30 wt %, 35 wt %, 40 wt%, 45 wt %, 50 wt %, 55 wt % or 60 wt % of the ER portion.

In one embodiment, the ER portion of the dosage form further comprises abinder. In another embodiment, the binder is selected from the groupconsisting of polyvinylpryolidone (povidone), a hydroxyalkylcellulosesuch as hydroxypropylcellulose, starches, pregelatinized starches,gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone,polyvinylalcohols, C12-C18 fatty acid alcohols, polyethylene glycol,polyols. In another embodiment, the ER portion of the dosage formcomprises a binder that is present in an amount that is about 2.0 wt %,2.5 wt %, 3.0 wt %, 3.5 wt %, 4.0 wt %, 4.5 wt %, 5.0 wt %, 5.5 wt %,6.0 wt %, 6.5 wt %, 7.0 wt %, 7.5 wt % or 8.0 wt % of the ER portion.

In one embodiment, the ER portion of the dosage form further comprises afiller. In another embodiment, the filler is selected frommicrocrystalline cellulose (MCC), dibasic calcium phosphate, tribasiccalcium phosphate, magnesium carbonate, magnesium oxide, calciumsilicate, polyvinylpirrolydone, dibasic calcium sulfate, tribasiccalcium sulfate, starch, calcium carbonate, magnesium carbonate,carbohydrates, modified starches, lactose, sucrose, mannitol, sorbitol,and inorganic compounds. In another embodiment, the ER portion of thedosage form comprises a filler that is present in an amount that isabout 1.0 wt %, 1.5 wt %, 2.0 wt %, 2.5 wt %, 3.0 wt %, 3.5 wt %, 4.0 wt%, 4.5 wt %, 5.0 wt %, 5.5 wt %, 6.0 wt %, 6.5 wt %, 7.0 wt %, 7.5 wt %,8.0 wt %, 8.5 wt %, 9.0 wt %, 9.5 wt % or 10 wt % of the ER portion ofthe dosage form.

In one embodiment, the ER portion of the dosage form further comprises alubricant. In another embodiment, the lubricant is magnesium stearate.In another embodiment, the ER portion of the dosage form comprises alubricant that is present in an amount that is about 0.1 wt %, 0.5 wt %,0.75 wt %, 1.0 wt %, 1.5 wt %, 1.75 wt %, 1.80 wt %, 1.85 wt %, 1.90 wt% or 2.0 wt % of the ER portion.

In one embodiment, the ER portion of the dosage form comprises ananti-oxidant which is ascorbic acid, citric acid, ascorbyl palmitate,butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, or propylgallate.In another embodiment, the antioxidant is present in the ER portion ofthe dosage form at a wt % ranging from about 0.10 wt % to about 0.20 wt%, or from about 0.05 wt % to about 0.30 wt %. In yet anotherembodiment, the antioxidant is present in the ER portion of the dosageform at a wt % of about 0.01 wt %, 0.05 wt %, 0.10 wt %, 0.15 wt %, 0.20wt %, 0.25 wt %, 0.35 wt %, 0.50 wt %, 0.75 wt %, 1.00 wt %, 2.00 wt %,3.00 wt % or 4.00 wt % of the ER portion.

In one embodiment, the ER portion of the dosage form comprises achelating agent. In another embodiment, the chelating agent is selectedfrom ethylenediamine tetracetic acid (EDTA) and its salts,N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid(NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,1,4,7,10-tetraazacyclodo-decane-N,N′,N″,N′″-tetraacetic acid,1,4,7,10-tetraaza-cyclododecane-N,N′,N″-triacetic acid,1,4,7-tris(carboxymethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazocyclodecane,1,4,7-triazacyclonane-N,N′,N″-triacetic acid,1,4,8,11-tetraazacyclotetra-decane-N,N′,N″,N′″-tetraacetic acid;diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,bis(aminoethanethiol)carboxylic acid, triethylenetetraamine-hexaaceticacid, and 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid. In afurther embodiment, the chelating agent is the sodium salt of EDTA. Inyet another embodiment, the ER portion of the dosage form comprises achelating agent which is present in an amount that is about 0.01 wt % toabout 0.10 wt % or about 0.02 to about 0.08 wt % of the ER portion. Inyet another embodiment, the ER portion of the dosage form comprises achelating agent which is present in an amount which is about 0.01 wt %,0.02 wt %, 0.03 wt %, 0.04 wt %, 0.05 wt %, 0.06 wt %, 0.07 wt %, 0.08wt %, 0.09 wt % or 0.10 wt %.

In one embodiment, the ER portion of the dosage form comprises a coloragent. In another embodiment, the color agent is present in an amountthat is about 2.0 wt % to about 5.0 wt % of the ER portion of the dosageform. In yet another embodiment, the color agent is present in an amountthat is about 1.0 wt %, 1.5 wt %, 2.0 wt %, 2.5 wt %, 3.0 wt %, 3.5 wt%, 4.0 wt %, 4.5 wt %, or 5.0 wt % of the ER portion.

In another embodiment, the ER portion of the dosage form comprisesparticles of acetaminophen admixed with the opioid and the polymer.

In one embodiment, the ER portion of the dosage form comprises particleswherein the particles have an average particle size greater than about20 microns and less than about 2000 microns, greater than about 50microns and less than about 1500 microns, greater than about 100 micronsand less than about 1000 microns, greater than about 150 microns andless than about 1000 microns, or greater than about 200 microns and lessthan about 2000 microns.

In one embodiment, the ER portion of the dosage form comprises particleswherein at least about 50% of the particles are greater than about 250microns in size. In another embodiment, about 20% to about 30% of theparticles are greater than about 150 microns and less than about 250microns.

In another embodiment, after oral administration to a subject, theopioid is released from ER portion of the dosage form at a rateproportional to release of the acetaminophen for a period of at leastabout 4 hours (h). In another embodiment, the proportional rate ofrelease occurs for a period of at least about 5 h, 6 h, 7 h, or 8 h. Inyet another embodiment, the first dose of opioid is released from the ERportion of the dosage form at a rate proportional to release of thefirst dose of acetaminophen for a period of about 4 h to about 8 h. Inanother embodiment, the proportional rate of release occurs over aperiod of about 5 h to about 6 h. In another embodiment, the ER portionof the dosage form comprises particles of acetaminophen admixed with theopioid and the polymer.

In some embodiments, the ER portion of the dosage form swells uponadministration to a size that is about 110% to about 160%, or about 120%to about 150%, or about 125% to about 145%, or about 130% to about 145%of the size of the dosage form within 30 minutes of administration. Inother embodiments, the ER portion of the dosage form swells to a sizethat is approximately 130% of the size of the dosage form within 30minutes of administration.

In another embodiment, upon administering of the dosage form to asubject, the dosage form provides at least about 4 hours to about 12hours of drug delivery to the upper gastrointestinal tract, whichincludes the stomach and the small intestine. In another embodiment, thedosage form provides at least 6 hours of drug delivery to the uppergastrointestinal tract. In yet a further embodiment, the dosage formprovides at least 8 hours of drug delivery to the upper gastrointestinaltract. In yet a further embodiment, the dosage form provides at least 9hours, 10 hours, 11 hours or 12 hours of drug delivery to the uppergastrointestinal tract.

In some embodiments, the dosage form provides a dissolution profilewherein for each of the first dose of acetaminophen and the first doseof the opioid, between about 40% to about 50% of the first dose remainsin the dosage form between about 1 and 2 hours after administration. Inone embodiment, not more than 50% of the first dose of acetaminophen andfirst dose of opioid is released within about the first hour. In afurther embodiment, not more than 45% or not more than 40% of the firstdose of acetaminophen and first dose of opioid is released within aboutthe first hour. In another embodiment, not more than 85% of the firstdose of acetaminophen and first dose of opioid is released within about4 hours. In another embodiment, not less than 50% is released afterabout 6 hours. In yet another embodiment, not less than 60% is releasedafter about 6 hours.

In one embodiment, the dosage form further comprises an IR portion. TheIR portion of the dosage form typically comprises a second dose of anopioid and a second dose of acetaminophen. In another embodiment, theopioid and the acetaminophen are dispersed in the IR portion of thedosage form. In yet another embodiment, a dosage form comprising an IRportion in contact with an ER portion is provided.

In one embodiment, the IR portion of the dosage form comprises about 50mg to about 900 mg, about 75 mg to about 700 mg, about 100 mg to about600 mg, or about 150 mg to about 250 mg of acetaminophen. In yet anotherembodiment, the IR portion of the dosage form comprises about 200 mg toabout 400 mg of acetaminophen. In yet another embodiment, the IR portionof the dosage form comprises about 180 mg, 190 mg, 195 mg, 200 mg, 205mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg or 235 mg of acetaminophen.

In another embodiment, the IR portion of the dosage form comprises about5 mg to about 60 mg, or about 10 mg to about 40 mg, or about 15 mg toabout 20 mg of the opioid. In yet another embodiment, the IR portion ofthe dosage form comprises about 14.0 mg, 14.5 mg, 15.0 mg, 15.5 mg, 16.0mg, 16.5 mg, or 17.0 mg of the opioid.

In another embodiment, the amount of acetaminophen in the IR portion istypically between about 10 to about 20, more typically between about 12to about 16 times the amount of opioid in the IR portion. In anotherembodiment, the ratio of acetaminophen to opioid in the IR portion isabout 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.

In yet another embodiment, the IR portion of the dosage form furthercomprises a binder. In some embodiments, the binder is selected from thegroup consisting of polyvinylpryolidone (povidone),hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol,hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose,methacrylic acid copolymers, ethyacrylate-methylmethacrylate copolymers,guar gum, arabic gum, xanthan gum, gelatine, pectin and mixturesthereof. In another embodiment, the binder is present in the IR portionof the dosage form in an amount that is about 4.5 wt %, 5.0 wt %, 5.5 wt%, 6.0 wt %, 6.5 wt %, 7.0 wt %, 7.5 wt %, 8.0 wt %, 8.5 wt %, 9.0 wt %,9.5 wt % or 10.0 wt % of the IR portion.

In one embodiment, the IR portion of the dosage form comprises ananti-oxidant which is ascorbic acid, citric acid, ascorbyl palmitate,butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, or propylgallate.In another embodiment, the antioxidant is present in the IR portion ofthe dosage form at a wt % ranging from about 0.10 wt % to about 0.40 wt%, or from about 0.05 wt % to about 0.35 wt %. In yet anotherembodiment, the antioxidant is present in the IR portion of the dosageform at a wt % of about 0.01 wt %, 0.05 wt %, 0.10 wt %, 0.15 wt %, 0.20wt %, 0.25 wt %, 0.30 wt %, 0.35 wt %, 0.50 wt %, 0.75 wt %, 1.00 wt %,2.00 wt %, 3.00 wt % or 4.00 wt % of the IR portion.

In one embodiment, the IR portion of the dosage form comprises achelating agent. In another embodiment, the chelating agent is selectedfrom ethylenediamine tetracetic acid (EDTA) and its salts,N-(hydroxy-ethyl)ethylenediaminetriacetic acid, nitrilotriacetic acid(NIA), ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,1,4,7,10-tetraazacyclodo-decane-N,N′,N″,N′″-tetraacetic acid,1,4,7,10-tetraaza-cyclododecane-N,N′,N″-triacetic acid,1,4,7-tris(carboxymethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazocyclodecane,1,4,7-triazacyclonane-N,N′,N″-triacetic acid,1,4,8,11-tetraazacyclotetra-decane-N,N′,N″,N′″-tetraacetic acid;diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,bis(aminoethanethiol)carboxylic acid, triethylenetetraamine-hexaaceticacid, and 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid. In yetanother embodiment, the IR portion of the dosage form comprises achelating agent which is present in an amount that is about 0.01 wt % toabout 0.10 wt % or about 0.02 to about 0.08 wt % of the IR portion. Inyet another embodiment, the IR portion of the dosage form comprises achelating agent which is present in an amount which is about 0.01 wt %,0.02 wt %, 0.03 wt %, 0.04 wt %, 0.05 wt %, 0.06 wt %, 0.07 wt %, 0.08wt %, 0.09 wt % or 0.10 wt %.

In one embodiment, the IR portion of the dosage form comprises particlesof acetaminophen granulated with the opioid and the binder.

In one embodiment, the IR portion of the dosage form comprises particleswherein the particles have an average particle size greater than about20 microns and less than about 2000 microns, greater than about 50microns and less than about 1500 microns, greater than about 100 micronsand less than about 1000 microns, greater than about 150 microns andless than about 1000 microns, or greater than about 200 microns and lessthan about 2000 microns.

In one embodiment, the ER portion of the dosage form comprises particleswherein at least about 50% of the particles are greater than about 250microns in size. In another embodiment, about 20% to about 30% of theparticles are greater than about 150 microns and less than about 250microns.

In one embodiment, the IR portion of the dosage form comprisesparticles, wherein at least 30% of the particles have a size greaterthan 250 microns (μ).

In one embodiment, the dosage form is a pharmaceutical tablet, such as agastric retentive tablet for the extended release of the opioid and theacetaminophen. In another embodiment, the tablet is a monolithic tabletcomprising an ER portion. In another embodiment, the tablet is amonolithic tablet comprising an ER portion and an IR portion. In anotherembodiment, the tablet is a bilayer tablet, comprising an ER portion andan IR portion. The bilayer tablet is typically a monolithic tablet. Inanother embodiment, the dosage form is a capsule comprising an ERportion. In another embodiment, the dosage form is a capsule comprisingER portion and an IR portion.

In one embodiment, the bilayer tablet has a friability of no greaterthan about 0.1%, 0.2% 0.3%, 0.4%, 0.5%, 0.7% or 1.0%. In anotherembodiment, the bilayer tablet has a friability of greater than 0 butless that about 1.0%, greater than 0 but less than about 0.5%, greaterthan 0 but less than about 0.3%, or greater than 0 but less than about0.2%.

In one embodiment, the bilayer tablet has a hardness of at least about10 kilopond (also known as kilopons) (kp). In some embodiments, thetablet has a hardness of about 9 kp to about 25 kp, or about 12 kp toabout 20 kp. In further embodiments, the tablet has a hardness of about11 kp, 12 kp, 13 kp, 14 kp, 15 kp, or 16 kp.

In one embodiment, the tablets have a content uniformity of from about85 to about 115 percent by weight or from about 90 to about 110 percentby weight, or from about 95 to about 105 percent by weight. In otherembodiments, the content uniformity has a relative standard deviation(RSD) equal to or less than about 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0% or0.5%.

In one embodiment, the dosage form comprises an opioid or an opioid-likecompound chosen from: adulmine, alfentanil, allocryptopine,allylprodine, alphaprodine, anileridine, aporphine, benzylmorphine,berberine, bicuculine, bicucine, bezitramide, buprenorphine,bulbocaprine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin,hydrocodone, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine,meptazinol, metazocine, methadone, metopon, morphine, myrophine,narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone,papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine,phenoperidine, piminodine, piritramide, propheptazine, promedol,properidine, propoxyphene, sufentanil, tilidine, tramadol, andpharmaceutical salts of any of the foregoing.

In one embodiment, acetaminophen can be present in the dosage form in anamount ranging from about 100 milligrams (mg) to about 1300 mg.

In another embodiment, acetaminophen is present in the dosage form at anamount of about 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg,325 mg, 350 mg, 400 mg, 425 mg, 450 mg, 500 mg, 525 mg, 530 mg, 535 mg,540 mg, 545 mg, 550 mg, 600 mg, 650 mg or about 700 mg.

In some embodiments, an opioid is present in the dosage form at anamount of about 5 mg, 7.5 mg, 10 mg, 12 mg, 15 mg, 20 mg, 22.5 mg, 25mg, 30 mg, 32 mg, 34 mg, 35 mg, 37 mg, 40 mg, 50 mg, 60 mg, 70 mg orhigher. In one embodiment, wherein the opioid is tramadol, an amount ofabout 5 mg to about 40 mg, about 10 mg to about 30 mg, or about 15 mg toabout 20 mg may be employed. In another embodiment, wherein the opioidis codeine, an amount of about 50 mg to about 300 mg, or about 75 mg toabout 200 mg, or about 120 mg to about 180 mg may be employed. In yetanother embodiment, wherein the opioid is oxycodone, an amount of 2 mgto about 100 mg, 5 mg to about 75 mg, about 5 mg to about 40 mg, about10 mg to about 30 mg, or about 15 mg may be employed. In yet anotherembodiment, wherein the opioid is hydrocodone, an amount of 2 mg toabout 80 mg, 5 mg to about 40 mg, about 10 mg to about 30 mg, or about15 to about 20 mg may be employed.

In another aspect, a pharmaceutical or gastric retentive oral dosageform comprising acetaminophen and an opioid, wherein the formulation isadministered to a mammal once in a 24 hour period (q.d. or once-daily),two times in a 24 hour period (b.i.d. or twice-daily) or three times ina 24 hour period (t.i.d. or three times daily) is provided.

Also provided, is a method of making a pharmaceutical or gastricretentive dosage form comprising a first dose of an opioid, a first doseof acetaminophen dispersed in an ER polymer matrix comprised of apolymer that swells upon imbibition of fluid to a size sufficient forgastric retention in the upper gastrointestinal tract in a fed mode.

In one embodiment, the method comprises wet granulation of a firstmixture that comprises an opioid, acetaminophen and a binder to producea first granulation mixture. In another embodiment, the wet granulatingcomprises spraying a solution of the binder and the opioid dissolved inwater onto acetaminophen particles. In a further embodiment, theparticles of the first granulation mixture are blended with a polymerand one or more excipients to form an ER portion of a dosage form.

In one embodiment, the one or more excipients blended with the firstgranulation mixture are chosen from among a filler, a lubricant and acolor agent.

In one embodiment, the wet granulation comprises making a solutioncontaining an opioid and a binder and spraying the solution onto theacetaminophen particles in a fluid bed granulator.

In a further embodiment, the method comprises compressing the ER portionof the dosage form into a tablet.

In one embodiment, the wet granulation of the ER portion of the dosageform produces particles with a bulk density ranging from about 0.30 to0.40 grams/milliliter (g/ml). In other aspects, the wet granulationproduces particles with a tap density ranging from about 0.35 g/ml toabout 0.45 g/ml. In other embodiments, the wet granulation producesparticles, wherein at least about 50% of the particles have a sizegreater than 250μ. In still other embodiments, the wet granulationproduces particles wherein about 20% to about 30% of the particles havea size greater than about 150μ and less than about 250μ.

In one embodiment, the method of making a pharmaceutical and/or gastricretentive oral dosage form comprising acetaminophen and an opioidfurther comprises wet granulating a second mixture comprising theacetaminophen, the opioid, and the binder to form a second granulationmixture. In a further embodiment, the second granulation mixture isblended with one or more excipients to produce an IR portion of thedosage form. In yet a further embodiment, the IR portion is compressedwith the ER portion of the dosage form to produce a bilayer tablet.

In further embodiments, wet granulating the second mixture is achievedby fluid bed granulation. In other embodiments, wet granulating thesecond mixture is achieved by a high shear granulation method.

In an alternative embodiment, the method of making a pharmaceuticaland/or gastric retentive oral dosage form comprising acetaminophen andan opioid comprises using a high-shear fluid bed granulator to prepare afirst granulation mixture which comprises an opioid, a filler, and afirst binder. In one embodiment, the first granulation mixture furthercomprises an antioxidant. In yet another embodiment, the firstgranulation mixture further comprises a metal ion chelator. In anotherembodiment, the method further comprises drying the first granulationmixture. In yet another embodiment, the method further comprises using afluid-bed granulator to prepare a second granulation mixture comprisingthe first granulation mixture and acetaminophen. In yet anotherembodiment, the method further comprises blending the second granulationmixture with a hydrophilic polymer and one or more excipients to form anextended release portion. In yet another embodiment, the method furthercomprises compressing the extended release portion of the dosage form toform a monolithic tablet.

In one embodiment, the method of making a pharmaceutical and/or gastricretentive oral dosage comprises using a fluid-bed granulator to preparea third granulation mixture which comprises the first granulationmixture, acetaminophen and a binder. In another embodiment, the methodfurther comprises blending the third granulation mixture with alubricant to form an immediate release portion. In yet anotherembodiment, the method further comprises compressing the extendedrelease portion and the immediate release portion to for a bilayertablet.

Also provided is a method of treating pain in a subject in need of suchtreatment comprising administering a therapeutic effective amount of anyof the describe dosage forms or pharmaceutical formulations herein.

In one embodiment, a gastric retained dosage form comprisingacetaminophen, an opioid and a swellable polymer is administered to asubject suffering from or diagnosed with a pain state. In otherembodiments, the subject is suffering from chronic pain. In yet anotherembodiment, the subject is suffering from acute pain. In yet otherembodiments, the subject is suffering from both chronic and acute pain.

In one embodiment, a gastric retained dosage form is administered to asubject in a fed mode. In another embodiment, the dosage form isadministered with a meal to a subject once in a 24 hour period. In otherembodiments, the dosage form is administered with a meal to the subjecttwice in a 24 hour period. In some embodiments, the dosage form isadministered with a meal to the subject three times in a 24 hour period.

Additional embodiments of the present method, compositions, and the likewill be apparent from the following description, drawings, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment or aspect. Additional aspects and embodiments are set forthin the following description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the dissolution profile of a 960mg tablet containing 650 mg acetaminophen, 30 mg phenylephrine, and24.28 wt % POLYOX® PEO N-60K.

FIG. 2 is a graphical representation of the dissolution profile of a 960mg tablet containing 650 mg acetaminophen, 30 mg phenylephrine, and24.28 wt % POLYOX® PEO 1105.

FIG. 3 is a graphical representation of the dissolution release profileof a 960 mg tablet containing 500 mg acetaminophen, 30 mg phenylephrine,24.22 wt % POLYOX® PEO N-60K and 16.60 wt % MCC.

FIG. 4 is a graphical representation of the dissolution release profileof a 960 mg tablet containing 500 mg acetaminophen, 30 mg phenylephrine,24.22 (wt %) POLYOX® PEO 1105 and 16.60 wt % MCC.

FIG. 5 is a graphical representation of the dissolution profile of a1000 mg tablet containing 31 weight percent POLYOX® PEO N-60K andvarying amounts of microcrystalline cellulose.

FIG. 6 is a graphical representation of the disintegration profile of a960 mg tablet containing 650 mg acetaminophen, 30 mg phenylephrine, and24.28 wt % POLYOX® PEO N-60K.

FIG. 7 is a graphical representation of the disintegration profile of a960 mg tablet containing 650 mg acetaminophen, 30 mg phenylephrine, and24.28 wt % POLYOX® PEO 1105.

FIG. 8 is a graphical representation of the disintegration releaseprofile of a 960 mg tablet containing 500 mg acetaminophen, 30 mgphenylephrine, 24.22 wt % POLYOX® PEO N-60K and 16.60 wt % MCC.

FIG. 9 is a graphical representation of the disintegration releaseprofile of a 960 mg tablet containing 500 mg acetaminophen, 30 mgphenylephrine, 24.22 wt % POLYOX® PEO 1105 and 16.60 wt % MCC.

FIG. 10 is a graphical representation of Phenylephrine (PE) release vs.the square root of time of a tablet having 24.28 wt % POLYOX® PEO N-60K(sample 1), and a tablet having 24.28 wt % POLYOX® PEO 1105 (sample 2).

FIG. 11 is a graphical representation of PE release vs. the square rootof time generated by a tablet having 24.22 wt % POLYOX® PEO N-60K and16.60 wt % MCC (sample 3) and a tablet having 24.22 wt % POLYOX® PEO1105 and 16.60 wt % MCC (sample 4).

FIG. 12 is a graphical representation of the cumulative oxycodonedisintegration release of tablets containing varying amounts of POLYOX®PEO N-60K or POLYOX® PEO 1105.

FIG. 13 is a graphical representation of the cumulative acetaminophendisintegration release of tablets containing varying amounts of POLYOX®PEO N-60K or POLYOX® PEO 1105.

FIG. 14 is a graphical representation of linear regression analysis ofoxycodone and acetaminophen release for a dosage form described herein(lot number: 081104-03).

FIG. 15 is a graphical representation of linear regression analysis ofoxycodone and acetaminophen release data for a dosage form as describedherein (lot number: 081104-06).

FIG. 16 is a graphical representation of the cumulative acetaminophenand oxycodone HCl disintegration release of a bilayer tablet.

FIG. 17 is a graphical representation of the cumulative acetaminophenand oxycodone HCl disintegration release of a bilayer tablet.

FIG. 18 is a graphical representation of the particle size distributionas determined for an extended release polymer matrix.

FIG. 19 is a graphical representation of the particle size distributionas determined for an IR portion of a dosage form.

FIG. 20 is a graphical representation of the cumulative acetaminophenand tramadol disintegration release of a bilayer tablet.

FIG. 21 is a graphical representation of the acetaminophen dissolutionrelease profile for a bilayer tablet in which the IR layer containshydroxypropylcellulose as a binder.

FIG. 22 is a graphical representation of the oxycodone hydrochloridedissolution release profile for a bilayer tablet in which the IR layercontains hydroxypropylcellulose as a binder.

FIG. 23 is a graphical representation of the cumulative acetaminophenand oxycodone HCl disintegration release of a bilayer tablet formulatedfor 8-hour release.

FIG. 24 is a graphical representation of the cumulative acetaminophenand oxycodone HCl disintegration release of a bilayer tablet formulatedfor 6-hour release.

FIG. 25 is a graphical representation of the cumulative acetaminophenand oxycodone HCl disintegration release of a bilayer tablet formulatedfor 8-hour release.

FIG. 26 is a graphical representation of the cumulative acetaminophenand oxycodone HCl disintegration release of a bilayer tablet formulatedfor 6-hour release.

FIG. 27 is a graphical representation of erosion of bilayer tabletscontaining acetaminophen and oxycodone HCl in vitro, in vivo and

DETAILED DESCRIPTION

The various aspects and embodiments will now be fully described herein.These aspects and embodiments may, however, be embodied in manydifferent forms and should not be construed as limiting; rather, theseembodiments are provided so the disclosure will be thorough andcomplete, and will fully convey the scope of the present subject matterto those skilled in the art.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

I. DEFINITIONS

It must be noted that, as used in this specification, the singular forms“a,” “an,” and “the” include plural referents unless the context clearlydictates otherwise.

The term “about,” particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

Compounds useful in the compositions and methods include those describedherein in any of their pharmaceutically acceptable forms, includingisomers such as diastereomers and enantiomers, salts, solvates, andpolymorphs, as well as racemic mixtures and pure isomers of thecompounds described herein, where applicable.

“Pharmaceutically acceptable salt” includes, but is not limited to,amino acid salts, salts prepared with inorganic acids, such as chloride,sulfate, phosphate, diphosphate, bromide, and nitrate salts, or saltsprepared from the corresponding inorganic acid form of any of thepreceding, e.g., hydrochloride, etc., or salts prepared with an organicacid, such as malate, maleate, fumarate, tartrate, succinate,ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate,ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, aswell as estolate, gluceptate and lactobionate salts. Similarly saltscontaining pharmaceutically acceptable cations include, but are notlimited to, sodium, potassium, calcium, aluminum, lithium, and ammonium(including substituted ammonium).

“Optional” or “optionally” means that the subsequently describedelement, component or circumstance may or may not occur, so that thedescription includes instances where the element, component, orcircumstance occurs and instances where it does not.

The terms “subject,” “individual” or “patient” are used interchangeablyherein and refer to a vertebrate, preferably a mammal. Mammals include,but are not limited to, humans.

The term “drug” or “active agent” is used herein to refer to anychemical that elicits a biochemical response when administered to ahuman or an animal. The drug may act as a substrate or product of abiochemical reaction, or the drug may interact with a cell receptor andelicit a physiological response, or the drug may bind with and block areceptor from eliciting a physiological response.

The term “sparingly soluble,” as used herein, refers to a drug having asolubility (measured in water at 37° C.) in the range of about 0.001% toabout 2% by weight, more preferably about 0.001% to about 0.5% byweight. The term “soluble,” as used herein, refers to a drug having asolubility (measured in water at 37° C.) in the range of about 2% toabout 10% by weight, more preferably about 2% to about 5% by weight.

The term “fed mode,” as used herein, refers to a state which istypically induced in a patient by the presence of food in the stomach,the food giving rise to two signals, one that is said to stem fromstomach distension and the other a chemical signal based on food in thestomach. It has been determined that once the fed mode has been induced,larger particles are retained in the stomach for a longer period of timethan smaller particles. Thus, the fed mode is typically induced in apatient by the presence of food in the stomach.

Administration of a dosage form “with a meal,” as used herein, refers toadministration before, during or after a meal, and more particularlyrefers to administration of a dosage form about 1, 2, 3, 4, 5, 10, 15minutes before commencement of a meal, during the meal, or about 1, 2,3, 4, 5, 10, 15 minutes after completion of a meal.

A drug “release rate,” as used herein, refers to the quantity of drugreleased from a dosage form or pharmaceutical composition per unit time,e.g., milligrams of drug released per hour (mg/hr). Drug release ratesfor drug dosage forms are typically measured as an in vitro rate ofdissolution, i.e., a quantity of drug released from the dosage form orpharmaceutical composition per unit time measured under appropriateconditions and in a suitable fluid. The specific results of dissolutiontests claimed herein are performed on dosage forms or pharmaceuticalcompositions in a USP Type II apparatus and immersed in 900 ml ofsimulated intestinal fluid (SIF) at pH 6.8 and equilibrated in aconstant temperature water bath at 37° C. Suitable aliquots of therelease rate solutions are tested to determine the amount of drugreleased from the dosage form or pharmaceutical composition. Forexample, the drug can be assayed or injected into a chromatographicsystem to quantify the amounts of drug released during the testingintervals.

The term “swellable polymer,” as used herein, refers to a polymer thatwill swell in the presence of a fluid. It is understood that a givenpolymer may or may not swell when present in a defined drug formulation.Accordingly, the term “swellable polymer” defines a structural featureof a polymer which is dependent upon the composition in which thepolymer is formulated. Whether or not a polymer swells in the presenceof fluid will depend upon a variety of factors, including the specifictype of polymer and the percentage of that polymer in a particularformulation. For example, the term “polyethylene oxide,” or “PEO” refersto a polyethylene oxide polymer that has a wide range of molecularweights. PEO is a linear polymer of unsubstituted ethylene oxide and hasa wide range of viscosity-average molecular weights. Examples ofcommercially available PEOs and their approximate molecular weights are:POLYOX® NF, grade WSR coagulant, molecular weight 5 million, POLYOX®grade WSR 301, molecular weight 4 million, POLYOX® grade WSR 303,molecular weight 7 million, and POLYOX® grade WSR N-60K, molecularweight 2 million. It will be understood by a person with ordinary skillin the art that an oral dosage form which comprises a swellable polymerwill swell upon imbibition of water or fluid from gastric fluid

The term “friability,” as used herein, refers to the ease with which atablet will break or fracture. The test for friability is a standardtest known to one skilled in the art. Friability is measured understandardized conditions by weighing out a certain number of tablets(generally 20 tablets or less), placing them in a rotating Plexiglasdrum in which they are lifted during replicate revolutions by a radiallever, and then dropped approximately 8 inches. After replicaterevolutions (typically 100 revolutions at 25 rpm), the tablets arereweighed and the percentage of formulation abraded or chipped iscalculated. The friability of the tablets, of the present invention, ispreferably in the range of about 0% to 3%, and values about 1%, or less,are considered acceptable for most drug and food tablet contexts.Friability which approaches 0% is particularly preferred.

The term “tap density” or “tapped density,” as used herein, refers to ameasure of the density of a powder. The tapped density of apharmaceutical powder is determined using a tapped density tester, whichis set to tap the powder at a fixed impact force and frequency. Tappeddensity by the USP method is determined by a linear progression of thenumber of taps.

The term “bulk density,” as used herein, refers to a property of powdersand is defined as the mass of many particles of the material divided bythe total volume they occupy. The total volume includes particle volume,inter-particle void volume and internal pore volume.

The term “capping,” as used herein, refers to the partial or completeseparation of top or bottom crowns of the tablet main body. Formultilayer tablets, capping refers to separation of a portion of anindividual layer within the multilayer tablet. Unintended separation oflayers within a multilayer tablet prior to administration is referred toherein as “splitting.”

The term “content uniformity,” as used herein refers to the testing ofcompressed tablets to provide an assessment of how uniformly themicronized or submicron active ingredient is dispersed in the powdermixture. Content uniformity is measured by use of USP Method (GeneralChapters, Uniformity of Dosage Forms), unless otherwise indicated. Aplurality refers to five, ten or more tablet compositions.

II. GASTRIC RETENTIVE EXTENDED RELEASE DOSAGE FORM

It has been surprisingly discovered that a pharmaceutically acceptablegastric retentive dosage form can be formulated to provide release inthe stomach of a combination of a sparingly soluble drug and a highlysoluble drug at rates proportional to one another over an extendedperiod of time. Described herein is a pharmaceutically acceptable dosageform for the treatment of pain in a subject, comprising an opioid andacetaminophen dispersed in a polymer matrix that, upon oraladministration, swells dimensionally unrestrained, with the imbibitionof fluid to a size sufficient for gastric retention in a stomach of asubject in a fed mode. In the presently described dosage form,acetaminophen is released from the dosage form through erosion and anopioid also present in the dosage form is released at a rateproportional to that of the acetaminophen. This proportional rate ofrelease may occur over a period of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 hoursor more.

Gastric retentive dosage forms described herein typically contain atleast one hydrophilic polymer in a water-swellable polymer matrix havingat least one drug dispersed therein. The polymer matrix, wherein the atleast one drug is dispersed, absorbs water, causing the matrix to swell,which in turn promotes retention of the dosage form in the uppergastrointestinal tract (GI) of a subject. In addition, the matricesbecome slippery, which provides resistance to peristalsis and furtherpromotes gastric retention.

The imbibition of water and subsequent swelling also allows drugs todiffuse out of the matrix, to be released from the matrix as a result ofphysical erosion, i.e., degradation, or a combination of the two.Whether the drugs are released via diffusion or erosion depends, inpart, on the solubility of the drug in the relevant environment

Thus, successful formulation of effective oral pharmaceutical dosageforms may be highly dependent upon the solubility of the incorporateddrugs. For example, compositions in a tablet may differ when the tabletcontains a high solubility drug as compared to when the tablet containsa low solubility drug.

With the dosage forms described herein, the rate at which the drugs arereleased by the gastric retentive dosage form into the gastrointestinaltract is largely dependent on the rate at and the degree to which thepolymer matrix swells and. The polymer used in the dosage forms of thepresent invention should not release the drug at too rapid a rate so asto result in a drug overdose or rapid passage into and through thegastrointestinal tract, nor should the polymer release drug too slowlyto achieve the desired biological effect. Thus, polymers that permit arate of drug release that achieves the requisite pharmacokinetics forboth the acetaminophen and the opioid for a desired duration, as may bedetermined using a USP Disintegration Test or Dissolution Test, aredetermined for use in the dosage forms described herein.

Polymers suitable for use in the dosage forms described herein includethose that both swell upon absorption of gastric fluid and graduallyerode over a time period of hours. Upon swelling of the polymer matrix,soluble drugs dispersed in the matrix will slowly dissolve in thepermeating fluid and diffuse out from the matrix. Drugs that are poorly,or sparingly, soluble are released primarily via erosion of the polymermatrix. Erosion initiates simultaneously with the swelling process, uponcontact of the surface of the dosage form with gastric fluid. Erosionreflects the dissolution of the polymer beyond the polymer gel-solutioninterface where the polymer has become sufficiently dilute that it canbe transported away from the dosage form by diffusion or convection.This may also depend on the hydrodynamic and mechanical forces presentin the gastrointestinal tract during the digestive process. Whileswelling and erosion occur at the same time, it is preferred herein thatdrug release should be erosion-controlled, meaning that the selectedpolymer should be such that complete drug release occurs primarily as aresult of erosion rather than swelling and dissolution. However,swelling should take place at a rate that is sufficiently fast to allowthe tablet to be retained in the stomach. At minimum, for an erosionalgastric retentive dosage form, there should be an extended period duringwhich the dosage form maintains its size before it is diminished byerosion. Furthermore, the polymer which imbibes fluid to form a gastricretained, extended release polymer matrix is any polymer that isnon-toxic, that swells in a dimensionally unrestricted manner uponimbibition of water, and that provides for sustained release of at leastone incorporated drug.

Suitable polymers for use in the present dosage forms may be linear,branched, dendrimeric, or star polymers, and include synthetichydrophilic polymers as well as semi-synthetic and naturally occurringhydrophilic polymers. The polymers may be homopolymers or copolymers, ifcopolymers, either random copolymers, block copolymers or graftcopolymers. Synthetic hydrophilic polymers useful herein include, butare not limited to: polyalkylene oxides, particularly poly(ethyleneoxide), polyethylene glycol and poly(ethylene oxide)-poly(propyleneoxide) copolymers; cellulosic polymers; acrylic acid and methacrylicacid polymers, copolymers and esters thereof, preferably formed fromacrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methylmethacrylate, ethyl methacrylate, and copolymers thereof, with eachother or with additional acrylate species such as aminoethyl acrylate;maleic anhydride copolymers; polymaleic acid; poly(acrylamides) such aspolyacrylamide per se, poly(methacrylamide), poly(dimethylacrylamide),and poly(N-isopropyl-acrylamide); poly(olefinic alcohol)s such aspoly(vinyl alcohol); poly(N-vinyl lactams) such as poly(vinylpyrrolidone), poly(N-vinyl caprolactam), and copolymers thereof; polyolssuch as glycerol, polyglycerol (particularly highly branchedpolyglycerol), propylene glycol and trimethylene glycol substituted withone or more polyalkylene oxides, e.g., mono-, di- andtri-polyoxyethylated glycerol, mono- and di-polyoxyethylated propyleneglycol, and mono- and di-polyoxyethylated trimethylene glycol;polyoxyethylated sorbitol and polyoxyethylated glucose; polyoxazolines,including poly(methyloxazoline) and poly(ethyloxazoline);polyvinylamines; polyvinylacetates, including polyvinylacetate per se aswell as ethylene-vinyl acetate copolymers, polyvinyl acetate phthalate,and the like, polyimines, such as polyethyleneimine; starch andstarch-based polymers; polyurethane hydrogels; chitosan; polysaccharidegums; zein; and shellac, ammoniated shellac, shellac-acetyl alcohol, andshellac n-butyl stearate.

Examples of polymers suitable for use in this invention are cellulosepolymers and their derivatives (such as for example,hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose,and microcrystalline cellulose, polysaccharides and their derivatives,polyalkylene oxides, polyethylene glycols, chitosan, poly(vinylalcohol), xanthan gum, maleic anhydride copolymers, poly(vinylpyrrolidone), starch and starch-based polymers, poly(2-ethyl-2-oxazoline), poly(ethyleneimine), polyurethane hydrogels, andcrosslinked polyacrylic acids and their derivatives. Further examplesare copolymers of the polymers listed in the preceding sentence,including block copolymers and grafted polymers.

The terms “cellulose” and “cellulosic” are used herein to denote alinear polymer of anhydroglucose. Preferred cellulosic polymers arealkyl-substituted cellulosic polymers that ultimately dissolve in thegastrointestinal (GI) tract in a predictably delayed manner. Preferredalkyl-substituted cellulose derivatives are those substituted with alkylgroups of 1 to 3 carbon atoms each. Examples are methylcellulose,hydroxymethyl-cellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, and carboxymethylcellulose. In terms oftheir viscosities, one class of preferred alkyl-substituted cellulosesincludes those whose viscosity is within the range of about 100 to about110,000 centipoise as a 2% aqueous solution at 20° C. Another classincludes those whose viscosity is within the range of about 1,000 toabout 4,000 centipoise as a 1% aqueous solution at 20° C.

The amount of polymer relative to the drug can vary, depending on thedrug release rate desired and on the polymer, its molecular weight, andexcipients that may be present in the formulation. The amount of polymerwill be sufficient however to retain at least about 50% of the drugswithin the matrix one hour after ingestion (or immersion in the gastricfluid). Preferably, the amount of polymer is such that at least 55%,60%, 65%, 70%, 75%, or 80% of the drugs remains in the extended releasematrix one hour after ingestion. The amount of polymer is such that atleast 20%, 25%, 30%, 35%, 40% or 45% of the drugs remains in theextended release matrix four hours after ingestion. The amount ofpolymer is such that at least 75%, 80%, or 85% of the drugs is releasedwithin six hours after ingestion. In all cases, however, the drugs willbe substantially all released from the matrix within about ten hours,and preferably within about eight hours, after ingestion, and thepolymeric matrix will remain substantially intact until all of the drugis released. The term “substantially intact” is used herein to denote apolymeric matrix in which the polymer portion substantially retains itssize and shape without deterioration due to becoming solubilized in thegastric fluid or due to breakage into fragments or small particles.

The water-swellable polymers can be used individually or in combination.Certain combinations will often provide a more controlled release of thedrug than their components when used individually. Examples arecellulose-based polymers combined with gums, such as hydroxyethylcellulose or hydroxypropyl cellulose combined with xanthan gum. Anotherexample is poly(ethylene oxide) combined with xanthan gum.

As discussed above, the gastric retentive nature and release profiles ofa dosage form will depend partially upon the molecular weight of theswellable polymer. The polymers are preferably of a moderate to highmolecular weight (900,000 Da to 4,000,000 Da) to enhance swelling andprovide control of the release of the opioid and acetaminophen viaerosion of the polymer matrix. An example of suitable polyethylene oxidepolymers are those having molecular weights (viscosity average) on theorder of 900,000 Da to 2,000,000 Da. Using a lower molecular weight(“MW”) polyethylene oxide, such as POLYOX™ 1105 (900,000 MW) release forboth drugs are higher. Using a higher molecular weight polyethyleneoxide (such as POLYOX™ N-60K (2,000,000 MW) or POLYOX™ WSR-301(4,000,000 MW) reduces the rate of release for both drugs. In oneembodiment of the invention, a hydroxypropylmethylcellulose polymer ofsuch molecular weight is utilized so that the viscosity of a 1% aqueoussolution is about 4000 cps to greater than 100,000 cps.

A typical dosage form should swell to approximately 115% of its originalvolume within 30 minutes after administration, and at a later timeshould swell to a volume that is 130% or more of the original volume.

The acetaminophen and opioid are dispersed within the polymeric matrixdescribed above. The acetaminophen as used herein is preferably a USPpowder. Such powders of acetaminophen are known in the art as difficultto compress into tablet forms. In alternative gastric retentive extendedrelease oral dosage forms comprising acetaminophen and an opioid, theacetaminophen used may be a milled form, for example, various COMPAP®compositions (Mallinckrodt, Inc.). In certain embodiments, the opioidanalgesic is selected from tramadol, oxycodone, hydrocodone,hydromorphone, oxymorphone, methadone, morphine, or codeine, orpharmaceutically acceptable salts thereof.

Dosage forms prepared for oral administration according to the presentdisclosure will generally contain other inactive additives (excipients)such as binders, lubricants, disintegrants, fillers, stabilizers,antioxidants, chelating agents, surfactants, coloring agents, and thelike. The excipients described below may be present in the ER layer, theIR layer or both layers.

Binders are used to impart cohesive qualities to a tablet, and thusensure that the tablet remains intact after compression. Suitable bindermaterials include, but are not limited to, starch (including corn starchand pregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone,cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, and the like), and Veegum.

Lubricants are used to facilitate tablet manufacture, promoting powderflow and preventing particle capping (i.e., particle breakage) whenpressure is relieved. Useful lubricants are magnesium stearate (in aconcentration of from 0.25 wt % to 3 wt %, preferably 0.2 wt % to 1.0 wt%, more preferably about 0.3 wt %), calcium stearate, stearic acid, andhydrogenated vegetable oil (preferably comprised of hydrogenated andrefined triglycerides of stearic and palmitic acids at about 1 wt % to 5wt %, most preferably less than about 2 wt %).

Disintegrants are used to facilitate disintegration of the tablet,thereby increasing the erosion rate relative to the dissolution rate,and are generally starches, clays, celluloses, algins, gums, orcrosslinked polymers (e.g., crosslinked polyvinyl pyrrolidone). Fillersinclude, for example, materials such as silicon dioxide, titaniumdioxide, alumina, talc, kaolin, powdered cellulose, and microcrystallinecellulose, as well as soluble materials such as mannitol, urea, sucrose,lactose, lactose monohydrate, dextrose, sodium chloride, and sorbitol.Solubility-enhancers, including solubilizers per se, emulsifiers, andcomplexing agents (e.g., cyclodextrins), may also be advantageouslyincluded in the present formulations.

Stabilizers, as well known in the art, are used to inhibit or retarddrug decomposition reactions that include, by way of example, oxidativereactions.

Chelating agents tend to form complexes with trace amount of heavy metalions inactivating their catalytic activity in the oxidation ofmedicaments. Chelating agents for use in the dosage forms describedherein include, but are not limited to, ethylenediamine tetracetic acid(EDTA) and its salts, N-(hydroxy-ethyl)ethylenediaminetriacetic acid,nitrilotriacetic acid (NIA),ethylene-bis(oxyethylene-nitrilo)tetraacetic acid,1,4,7,10-tetraazacyclodo-decane-N,N′,N″,N′″-tetraacetic acid,1,4,7,10-tetraaza-cyclododecane-N,N′,N″-triacetic acid,1,4,7-tris(carboxymethyl)-10-(2′-hydroxypropyl)-1,4,7,10-tetraazocyclodecane,1,4,7-triazacyclonane-N,N′,N″-triacetic acid,1,4,8,11-tetraazacyclotetra-decane-N,N′,N″,N′″-tetraacetic acid;diethylenetriamine-pentaacetic acid (DTPA), ethylenedicysteine,bis(aminoethanethiol)carboxylic acid, triethylenetetraamine-hexaaceticacid, and 1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid.

Anti-oxidant may increase the stability of the dosage form by increasingthe stability of the active ingredient as well as the dosage form as awhole. The anti-oxidant may be selected from ascorbic acid, citric acid,ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodiumisoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate,sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E,4-chloro-2,6-ditertiarybutylphenol, alphatocopherol, or propylgallate,or any combination of the above.

The formulations are typically in the form of tablets. Otherformulations contain the matrix/active agent particles in capsules. Theencapsulating material should be highly soluble so that the particlesare freed and rapidly dispersed in the stomach after the capsule isingested. Such dosage forms are prepared using conventional methodsknown to those in the field of pharmaceutical formulation and describedin the pertinent texts, e.g., in Gennaro, A. R., editor. “Remington: TheScience & Practice of Pharmacy”, 21st ed., Williams & Williams, and inthe “Physician's Desk Reference”, 2006, Thomson Healthcare.

The tablets described herein may have individual layers containing oneor both drugs for delivering the component drug(s) in the immediaterelease or the extended release mode. For example, a layer for immediaterelease of acetaminophen or both acetaminophen and opioid can be addedto the layer containing both drugs for extended release. As toacetaminophen in this embodiment, although at steady state, unlikesingle dose administration, bioavailability is quite constant betweenthe doses of 325 mg and 2000 mg. This may be desirable for prompt reliefor bioavailability enhancement due to first-pass metabolism ofacetaminophen or the particular opioid.

Alternative gastric retentive drug delivery systems include theswellable bilayer described by Franz, et al., U.S. Pat. No. 5,232,704;the multi-layer tablet with a band described by Wong, et al., U.S. Pat.No. 6,120,803; the membrane sac and gas generating agent described inSinnreich, U.S. Pat. No. 4,996,058; the swellable, hydrophilic polymersystem described in Shell, et al., U.S. Pat. No. 5,972,389, and Shell,et al., WO 9855107, and the pulsatile gastric retentive dosage form byCowles et al., U.S. Pub. No. 2009/0028941, all of which are incorporatedherein by reference.

A bilayer tablet can be made with one layer containing only the opioidand the second layer containing only the acetaminophen if asubstantially different release profile for each drug is desired if thetwo drugs are not chemically compatible.

It is also envisioned that a third layer containing one or more drugsfor immediate release can be added to the dosage form.

Thus, the dosage forms provide controlled delivery of acetaminophen, andan opioid analgesic to the upper GI tract by a polymer matrix thatswells unrestrained dimensionally, and is retained in the stomach whentaken with food, i.e., in the fed mode. In an environment of use, thedosage forms swell on contact with water from gastric fluid due to thecomponent hydrophilic polymers, (for example, polyethylene oxide and/orhypromellose), and increase in size to be retained in the fed stomach.Acetaminophen and an opioid, for example oxycodone, hydrocodone, orcodeine, will be released from these gastric retained dosage forms overan extended period of time, about 3 to about 12 hours, preferably about4 to about 9 hours, more preferably at least about 5 hours, to the uppergastrointestinal (GI) tract where acetaminophen, and potentially theopioid, is best absorbed,

It is also notable that the presence of an opioid in a gastric retentivedosage form may adversely affect the ability of a dosage form to erodeat a rate that allows the desired release rates for the active agents.This is due to the fact that administration of opioids is known toreduce gastric motility (Nimmo et al., Br. J. Clin. Pharmac. (1975)2:509-513). The reduced gastric motility, in turn, may reduce theability of the dosage form to erode and release the drug within theerodible matrix.

Studies presented herein show that co-administration to dogs of agastric retentive dosage form and a solution of opioid in amounts tosimulate release by the embodied immediate release component have nosignificant effects on erosion of the gastric retentive extended releasedosage forms. Furthermore, studies are done with the disclosed gastricretentive tablet which comprises both the extended release and immediaterelease drug layers to show the presence of opioid in the describeddosage forms does not significantly affect erosion of the tablets in thedog stomach.

The pharmaceutically acceptable dosage form described herein furthercomprises an immediate release component. The immediate releasecomponent comprises acetaminophen and an opioid at lower amounts ascompared to the amounts of the opioid and the acetaminophen the gastricretained extended release portion of the dosage form. In another aspect,the amount of acetaminophen in generally between about 10 to 20, moretypically between 12 to 16 times the amount of opioid in the immediaterelease component.

In a preferred aspect, the immediate release component is in contactwith the extended release component.

The immediate release component may further comprise excipients such asbinders, lubricants, disintegrants, fillers, stabilizers, surfactants,coloring agents, and the like, as described above for the extendedrelease component.

The immediate release component may release at least 80-100% of theactive agents within the first hour of oral administration.

Is it understood by the skilled artisan that delivery time or durationof drug release by a particular dosage form is distinct from theduration of drug delivery by the dosage form. As an example, while anextended release dosage form may release one or more drugs over a periodof 3, 4 or more hours, depending on the half-life of the drug and thetime of transit of that drug through the gastrointestinal tract, therelevant sites of absorption will be exposed for a period of time beyondthe time of drug release from the dosage form. Thus, for example, adosage form that releases one or more drugs over a period ofapproximately 8 hours may be providing delivery of that drug for aperiod of approximately 12 hours.

The dosage form, as presently described, possesses the additionaladvantageous feature of being formulated as a standard oral dosage size,then after administration, imbibing water from the gastric fluid andswelling to a size large enough to be retained in the stomach in a fedmode.

III. METHODS FOR MAKING SOLID DOSAGE FORMS

The presently described dosage forms provide for extended release ofboth acetaminophen and an opioid in the stomach at rates proportional toone another wherein the dosage forms are comprised of a polymer matrixthat swells upon imbibition of fluid to a size sufficient for gastricretention. Thus, in formulating the dosage forms, it is critical toprovide the properties which simultaneously allow: a) an extent ofswelling to provide gastric retention over an extended period, and b) arate of swelling and erosion that allows extended and proportionalrelease of both a highly soluble and poorly soluble drug.

Furthermore, the formulation of these pharmaceutical oral dosage formspreferably result in final products that meet the requirements of theFood and Drug Administration (FDA). For example, final productspreferably have a stable product that does not fracture during storageand transport. This is measured, in part, in terms of friability andhardness. Dosage forms preferably also meet the requirements for contentuniformity, which essentially means that the dispersion of the activeingredient(s) is uniform throughout the mixture used to make the dosageform, such that the composition of tablets formed from a particularformulation does not vary significantly from one tablet to another. TheFDA requires a content uniformity within a range of 95% to 105%.Moreover, the active ingredients within the dosage forms should remainstable for long periods of time as required for standard consumer use.For example, it is very helpful to provide formulations that protect theactive ingredients from undergoing, for example, oxidative degradation.

It is significant to note that acetaminophen can be a particularlychallenging pharmaceutical ingredient with which to formulate solid oraldosage forms. Acetaminophen powders are difficult to compress into atablet form which will not break or fall apart.

The ability to formulate a pharmaceutical oral dosage form which bothdelivers the desired therapeutically effective ingredient and meets FDArequirements depends, in part, upon the process by which the product ismade.

In the case of tablets, as disclosed herein, a first step may involvethe granulation. How the granulation is carried out has great impact onthe properties of the final product.

Granulation is a manufacturing process which increases the size andhomogeneity of active pharmaceutical ingredients and excipients whichcomprise a solid dose formulation. The granulation process, which isoften referred to as agglomeration, changes important physicalcharacteristics of the dry formulation, with the aim of improvingmanufacturability and, thereby, product quality, as well as providingdesired release kinetics. As an example, water-soluble active agents maybe granulated with dissolution-retarding materials such as polymers toprovide an additional barrier. Such a process may reduce therelease-rate of a water-soluble active agent. In the presentembodiments, wherein the dosage form comprises a poorly soluble activeagent (e.g., acetaminophen) with a highly soluble opioid (e.g.,oxycodone HCl), the opioid may be granulated separately from the poorlysoluble agent in order to retard the dissolution of the opioid.Moreover, depending upon the polymers applied to the water-solubleactive agent, the extent of the diffusion rate of the active agentswithin a polymer (e.g., PolyOx) matrix may be manipulated to produce thedesired release profiles, i.e., one may individually control the releaserates of multiple active agents within a dosage form, wherein the activeagents have different solubilities. Dissolution-retarding componentsinclude, but are not limited to, water soluble or non-water solublepolymers, hydrogel polymers, pH sensitive polymers or any combinationthereof in a desired ratio.

Granulation technology can be classified into one of two basic types:Wet granulation and dry granulation. Wet granulation is by far the moreprevalent agglomeration process utilized within the pharmaceuticalindustry.

Most wet granulation procedures follow some basic steps; the drug(s) andexcipients are mixed together, and a binder solution is prepared andadded to the powder mixture to form a wet mass. The moist particles arethen dried and sized by milling or by screening through a sieve. In somecases, the wet granulation is “wet milled” or sized through screensbefore the drying step. There are four basic types of wet granulation;high shear granulation, fluid bed granulation, extrusion andspheronization and spray drying.

A. Fluid Bed Granulation

The fluid bed granulation process involves the suspension ofparticulates within an air stream while a granulation solution issprayed down onto the fluidized bed. During the process, the particlesare gradually wetted as they pass through the spay zone, where theybecome tacky as a result of the moisture and the presence of binderwithin the spray solution. These wetted particles come into contactwith, and adhere to, other wetted particles resulting in the formationof particles.

A fluid bed granulator consists of a product container into which thedry powders are charged, an expansion chamber which sits directly on topof the product container, a spray gun assembly, which protrudes throughthe expansion chamber and is directed down onto the product bed, and airhandling equipment positioned upstream and downstream from theprocessing chamber.

The fluidized bed is maintained by a downstream blower which createsnegative pressure within the product container/expansion chamber bypulling air through the system. Upstream, the air is “pre-conditioned”to target values for humidity, temperature and dew point, while specialproduct retention screens and filters keep the powder within the fluidbed system.

As the air is drawn through the product retention screen it “lifts” thepowder out of the product container and into the expansion chamber.Since the diameter of the expansion chamber is greater than that of theproduct container, the air velocity becomes lower within the expansionchamber. This design allows for a higher velocity of air to fluidize thepowder bed causing the material to enter the spray zone wheregranulation occurs before loosing velocity and falling back down intothe product container. This cycle continues throughout the granulationprocess.

The fluid bed granulation process can be characterized as having threedistinct phases; pre-conditioning, granulation and drying. In theinitial phase, the process air is pre-conditioned to achieve targetvalues for temperature and humidity, while by-passing the productcontainer altogether. Once the optimal conditions are met, the processair is re-directed to flow through the product container, and theprocess air volume is adjusted to a level which will maintain sufficientfluidization of the powder bed. This pre-conditioning phase completeswhen the product bed temperature is within the target range specifiedfor the process.

In the next phase of the process, the spraying of the granulatingsolution begins. The spray rate is set to a fall within a pre-determinedrange, and the process continues until all of the solution has beensprayed into the batch. It is in this phase where the actualgranulation, or agglomeration, takes place.

Once the binder solution is exhausted, the product continues to befluidized with warm process air until the desired end-point for moisturecontent is reached. This end-point often correlates well with productbed temperature, therefore in a manufacturing environment, the processcan usually be terminated once the target product bed temperature isreached. A typical fluid bed process may require only about thirty toforty-five minutes for the granulation step, plus ten to fifteen minuteson either side for pre-conditioning and drying.

As with any of the wet granulation processes, the most importantvariable is the amount of moisture required to achieve successfulagglomeration. The fluid bed granulation process requires a“thermodynamic” balance between process air temperature, process airhumidity, process air volume and granulation spray rate. While higherprocess air temperature and process air volume add more heat to thesystem and remove moisture, more granulating solution and a highersolution spray rate add moisture and remove heat via evaporativecooling. These are the critical process parameters which preferably areevaluated as a manufacturing process is developed, and the key isunderstanding the interdependency of each variable.

Additional factors affecting the outcome of the fluid bed granulationprocess are the amount and type of binder solution, and the method bywhich the binder is incorporated within the granulation. However, themost important process variables are the total amount of moisture addedthrough the process, and the rate at which the moisture content isincreased. These parameters can have a significant effect on the qualityand the characteristics of the granulation. For instance, a wetter fluidbed granulation process tends to result in a stronger granule with ahigher bulk density. However, an overly aggressive process, wheremoisture is added too rapidly, can loose control over achieving thefinal particle size and particle size distribution objectives.

“Fluid-bed granulating,” as used herein, refers to the method ofpreparing granules using a fluid bed granulation process as understoodby one having ordinary skill in the art.

B. High Shear Granulation

Most pharmaceutical products manufactured by wet granulation utilize ahigh shear process, where blending and wet massing are accomplished bythe mechanical energy generated by an impeller and a chopper. Mixing,densification and agglomeration are achieved through the “shear” forcesexerted by the impeller; hence the process is referred to as high sheargranulation.

“High shear granulating,” as used herein, refers to the method ofpreparing granules using a high shear granulation process as understoodby one having ordinary skill in the art.

The process begins by adding the dry powders of the formulation to thehigh shear granulator, which is a sealed “mixing bowl” with an impellorwhich rotates through the powder bed, and a chopper blade which breaksup over-agglomerates which can form during the process. There aretypically three phases to the high shear process; dry mixing, solutionaddition, or wet massing and high shear granulation.

In the first phase, dry powders are mixed together by the impeller bladewhich rotates through the powder bed. The impeller blade is positionedjust off the bottom of the product container. There is a similartolerance between the tips of the impeller blade and the sides of thecontainer. The impeller blades rotation trough the powder bed creates a“roping” vortex of powder movement. The dry mixing phase typically lastsfor only a few minutes.

In the second phase of the process, a granulating liquid is added to thesealed product container, usually by use of a peristaltic pump. Thesolution most often contains a binder with sufficient viscosity to causethe wet massed particles to stick together or agglomerate. It is commonfor the solution addition phase to last over a period of from three tofive minutes. While the impeller is rotating rather slowly during thisstep of the process, the chopper blade is turning at a fairly high rateof speed, and is positioned within the product container to chop upover-sized agglomerates, while not interfering with the impellersmovement.

Once the binder solution has been added to the product container, thefinal stage of the granulation process begins. In this phase, high shearforces are generated as the impeller blades push through the wet massedpowder bed, further distributing the binder and intimately mixing theingredients contained therein. The impeller and chopper tool continue torotate until the process is discontinued when the desired granuleparticle size and density end-points are reached. This end-point isoften determined by the power consumption and/or torque on the impeller.

Once the high shear granulation process has been completed, the materialis transferred to a fluid bed dryer, or alternatively, spread out ontotrays which are then placed in a drying oven, where the product is drieduntil the desired moisture content is achieved, usually on the order of1-2% as measured by Loss On Drying technique.

The most important variable which affects the high shear process is theamount of moisture required to achieve a successful granulation. A keyto the process is having the right amount of moisture to allow foragglomeration to occur. Too little moisture will result in anunder-granulated batch, with weak bonds between particles and smaller,to non-existent particles, with properties similar to those of the drypowder starting materials. On the other hand, excess moisture can resultin a “crashed” batch with results varying from severe over-agglomerationto a batch which appears more like soup.

Other critical formulation parameters affecting the outcome of the highshear granulation process are the amount and type of binder solution,and the method by which the binder is incorporated within thegranulation. For example, it is possible to include some of the binderin the dry powder mixture as well as in the granulating solution, or itmay be incorporated only in the granulating solution or only in the drypowder, as is the case where water is used as the granulating solution.

The high shear granulation process parameters which are variable includeimpeller and chopper speeds, the solution addition rate, and the amountof time allocated to the various phases of the process. Of these, themost important variables are the solution addition rate and the amountof time the wet massed product is under high shear mixing

C. Extrusion and Spheronization

This specialized wet granulation technique involves multiple processingsteps and was developed to produce very uniform, spherical particlesideally suited for multi-particulate drug delivery of delayed andsustained release dosage forms.

Similar to high shear granulation initially, the first step involves themixing and wet massing of the formulation. Once this step is complete,the wet particles are transferred to an extruder which generates veryhigh forces used to press the material out through small holes in theextruder head. The extrudate is of uniform diameter and is thentransferred onto a rotating plate for spheronization. The forcesgenerated by the rotating plate initially break up the extrudedformulation strands into uniform lengths. Additional dwell time withinthe spheronizer creates particles which are quite round and very uniformin size. These pellets or spheres may then be dried to the targetmoisture content, usually within a fluid bed system.

Particles produced in this manner tend to be very dense, and have acapacity for high drug loading, approaching 90% or more in some cases.Importantly, the particle size is very uniform, and the sizedistribution is very narrow, as compared to other granulationapproaches. This quality assures consistent surface area within andbetween batches, which is extremely important when functional coatingsare subsequently applied to create sustained release formulations,delayed release formulations and formulations designed to target aspecific area within the body.

Uniform surface area is important because the pharmaceutical coatingprocess endpoint is determined not by coating thickness, but by thetheoretical batch weight gain of the coating material. If the batchsurface area is consistent, then the coating thickness will also beconsistent for a given weight gain, and coating thickness is the primaryvariable in determining the functionality of the coating system, whetherthe goal is controlling the duration of sustained release formulationsor imparting an acid resistant characteristic to “beads” necessary toprotect certain compounds which would otherwise be severely degraded inthe presence of the acidic environment of the stomach.

D. Spray Drying

Spray drying is a unique and specialized process which converts liquidsinto dry powders. The process involves the spraying of very finelyatomized droplets of solution into a “bed” or stream of hot process airor other suitable gas. Not typically utilized for the conventionalgranulation of dosage form intermediates, spray drying has gainedacceptance within the industry as a robust process which can improvedrug solubility and bioavailability.

Spray drying can be used to create co-precipitates of a drug/carrierwhich can have improved dissolution and solubility characteristics. Inaddition, the process can also be useful as a processing aid. Forexample, it is much more difficult to maintain the uniformity of a drugin suspension, as compared to the same compound in solution. One mayhave a need to develop an aqueous coating or drug layering processutilizing a drug which is otherwise not soluble in water. By creating aco-precipitate of the drug and a suitable water soluble carrier, often alow molecular weight polymer, the co-precipitate will remain in solutionthroughout the manufacturing process, improving uniformity of the spraysolution and the dosage form created by the coating process. Uniformityis particularly important where lower doses of potent compounds areintended to be coated onto beads or tablet cores.

This same process may be used to enhance the solubility andbioavailability of poorly soluble drugs. By complexing certainexcipients and the active ingredient within a solvent system which isthen spray dried, it is possible to enhance the drugs absorption withinthe body. Selection of the solvent system, the complexing agent(s) andthe ratios utilized within the formulation are all important formulationvariables which determine the effectiveness of solubility enhancementutilizing the spray drying technique. Important process parameters whichalso have a profound effect on drug solubility are the temperatures ofthe spray solution and process gas, the spray rate and droplet size andthe rate of re-crystallization. The spray dried granulations created bythese techniques can then be incorporated into capsules or tablets byconventional manufacturing processes.

E. Dry Granulation

The dry granulation process involves three basic steps; the drug(s) andexcipients(s) are mixed (along with a suitable binder if needed) andsome form of lubrication, the powder mixture is compressed into dry“compacts,” and then the compacts are sized by a milling step. The twomethods by which dry granulation can be accomplished are slugging androller compaction.

IV. METHODS OF MAKING THE EXTENDED RELEASE GASTRIC RETENTIVE DOSAGEFORMS DISCLOSED HEREIN

In one aspect, a method of making a gastric retentive extended-releasedosage form as a single layer tablet comprising wet granulation of theopioid and the acetaminophen with the binder is provided. The wetgranulation can be a fluid-bed or high shear granulation method. Thegranulated particles are then blended with additional excipients asneeded to form a mixture which is then compressed to form tablets.

Extended release polymer matrices comprising acetaminophen and an opioidare made using either POLYOX™ 1105 (approximate molecular weight of900,000 Daltons), POLYOX™ N-60K (approximate molecular weight of2,000,000 Daltons), or POLYOX™WSR-301 (approximate molecular weight of4,000,000 Daltons). Prior to compression, components are granulatedusing a top spray fluid bed granulator A solution of povidone (PVP) inwater is sprayed onto the acetaminophen and fluid-bed granulated.

After fluid bed granulation and drying of the resultant particles,batches are characterized with respect to properties such as final Losson Drying (LOD), bulk density, tap density, and particle size.

Loss on Drying (LOD) is determined after each granulation using theMoisture Analyzer. A 1 g samples are taken and loaded into the moistureanalyzer. The sample is run for 5 minutes at a temperature of 105° C.

Bulk and tap densities can be determined as follows. A graduatedcylinder is filled with a certain amount of material (82-88 g), and thevolume recorded to determine the material bulk density. Tap density canbe determined with a help of a Tap Density Tester by exposing thematerial to 100 taps per test and recording the new volume.

Particle size determination is performed immediately after granulation,after sieving through 20 mesh screen to remove agglomerates. Particlediameter is determined with a sieve-type particle diameter distributiongauge using sieves with openings of 44, 53, 75, 106, 150, and 250 mesh.Fractions are weighed on Mettler balance to estimate size distribution.This provides determination of the quantitative ratio by particlediameter of composition comprising extended release particles. Sieveanalysis according to standard United States Pharmacopoeia methods(e.g., USP-23 NF 18), may be done such as by using a Meinzer II SieveShaker.

The granulated mixture can be blended with the polymer, filler andlubricant in a V-blender. The resultant mixture can be compressed intomonolithic, single-layer tablets using a Manesty® BB4 press, with amodified oval 0.3937″ width×0.6299″ length×0.075″ cup depth tool.Tablets may be prepared at a rate, for example, of approximately 800tablets per minute.

Tablets are then characterized with respect to disintegration anddissolution release profiles as well as tablet hardness, friability andcontent uniformity.

In vitro dissolution profiles for the tablets may be determined in USPapparatus (40 mesh baskets), 100 rpm, in pH 5.8 phosphate buffer (0.1 NHCl), 37° C. Samples of 5 ml at each time-point, may be taken withoutmedia replacement at 1, 2, 4, 6, 8 and 12 hours. In some embodiments,the dissolution profiles may be determined at varying pH values, such asat a pH of about 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 or 6.5. The fluidused may be, for example, HCl, phosphate buffer or simulated gastricfluid. The resulting cumulative dissolution profiles for the tabletsare, based upon a theoretical percent active added to the formulations.

A tablet preferably disintegrates before it dissolves. A disintegrationtester measures the time it takes a tablet to break apart in solution.The tester suspends tablets in a solution bath for visual monitoring ofthe disintegration rate. Both the time to disintegration and thedisintegration consistency of all tablets are measured. Thedisintegration profile may be determined in a USP Disintegration Testerin pH 5.8 phosphate buffer. In some embodiments, the disintegrationprofiles may be determined at varying pH values, such as at a pH ofabout 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0 or 6.5. The fluid used may be,for example, HCl, phosphate buffer, or simulated gastric fluid. Samples,1 ml at each time-point, may be taken, for example, without mediareplacement at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 hours. The resultingcumulative disintegration profiles are based upon a theoretical percentactive added to the formulation is determined.

Tablet hardness changes rapidly after compression as the tablet cools. Atablet that is too hard may not break up and dissolve into solutionbefore it passes through the body. In the case of the presentlydisclosed gastric retentive dosage forms, a tablet that is too hard maynot be able to imbibe fluid rapidly enough to prevent passage throughthe pylorus in a stomach in a fed mode. A tablet that is too soft maybreak apart, not handle well, and can create other defects inmanufacturing. A soft tablet may not package well or may not staytogether in transit.

After tablets are formed by compression, it is desired that the tabletshave a strength of at least 9-25 Kiloponds (Kp)/cm², preferably at leastabout 12-20 (Kp)/cm². A hardness tester is used to determine the loadrequired to diametrically break the tablets (crushing strength) into twoequal halves. The fracture force may be measured using a Venkel TabletHardness Tester, using standard USP protocols.

Friability is a well-known measure of a tablet's resistance to surfaceabrasion that measures weight loss in percentage after subjecting thetablets to a standardized agitation procedure. Friability properties areespecially important during any transport of the dosage form as anyfracturing of the final dosage form will result in a subject receivingless than the prescribed medication. Friability can be determined usinga Roche Friability Drum according to standard USP guidelines whichspecifies the number of samples, the total number of drum revolutionsand the drum rpm to be used. Friability values of from 0.8 to 1.0% areregarded as constituting the upper limit of acceptability.

The prepared tablets are tested for content uniformity to determine ifthey meet the pharmaceutical requirement of <6% relative standarddeviation (RSD). Each tablet is placed in a solution of 1.0 N HCl andstirred at room temperature until all fragments have visibly dissolved.The solution containing the dissolved tablet is analyzed by HPLC.

In another aspect, a method of making a bilayer tablet comprising agastric retentive extended-release layer and an immediate release layeris provided. In a further aspect, the gastric retentive extended-releaselayer is wet-granulated using the fluid bed or high shear granulationprocess. In yet a further aspect, the immediate release layer iswet-granulated using the fluid bed or high shear granulation process.

In another aspect, a dosage form for release of acetaminophen and anopioid is provided. The dosage form has an immediate release componentand an extended release component, each of the components comprisingacetaminophen and an opioid. The dosage form when placed in a USPDisintegration test with 800 mL aqueous buffer at pH 1.2 (0.1 N HCl) at37° C. apparatus provides an in vitro release of acetaminophen ratewherein 40-65% acetaminophen is released after 1 hour, 55-80%acetaminophen is released after 2 hours and at least about 75%acetaminophen is released after 6 hours. In one embodiment, the amountof opioid released is within about 20%, more preferably 15%, still morepreferably within about 10% or 5% of the amount of acetaminophenreleased between 1-6 hours, more preferably 1-8 hours.

In another embodiment, the immediate release component of the dosageform releases at least about 70% of the dose of acetaminophen in theimmediate release component after 1 hour in a USP disintegration testerwith 800 mL aqueous buffer at pH 1.2 at 37° C. and at least about 70% ofthe dose of opioid in the same test. In another embodiment, thecontrolled release component of the dosage form releases at least about40% of the dose of acetaminophen in the controlled release componentafter 6 hours and at least about 70% of the dose of acetaminophen in thecontrolled release component after 10 hours, when tested in a USPdisintegration tester with 800 mL aqueous buffer at pH 1.2 at 37° C. Thedose opioid released from the controlled release component is withinabout 20%, more preferably 15%, still more preferably within about 10%or 5% of the amount of acetaminophen released from the controlledrelease component over the desired period of sustained delivery,typically up to 6 hours, more preferably 8 hours.

In still another embodiment, the dosage form is a tablet comprised of animmediate release layer in direct contact with a sustained release,gastric retentive layer. The tablet when placed in a USP Disintegrationtest apparatus with 800 mL aqueous buffer at pH 1.2 (0.1 N HCl) at 37°C. provides an in vitro release such that between 40-65% acetaminophenis released after 1 hour, more preferably between 45-60%, and the amountof opioid released is within about 15%, 10%, or 5% of the amount ofacetaminophen released; and between 55-80% acetaminophen is releasedafter 2 hours, more preferably between 60-75%, and the amount of opioidreleased is within about 15%, 10%, or 5% of the amount of acetaminophenreleased at this time point.

In still another embodiment, the dosage form is a tablet comprised of animmediate release layer in direct contact with a sustained release,gastric retentive layer. The tablet when placed in a USP Disintegrationtest apparatus with 800 mL aqueous buffer at pH 1.2 (0.1 N HCl) at 37°C. provides an in vitro release such that between 10-25% acetaminophenis released after 1 hour, and the amount of opioid released is withinabout 15%, 10%, or 5% of the amount of acetaminophen released; andbetween 30-45% acetaminophen is released after 2 hours, and the amountof opioid released is within about 15%, 10%, or 5% of the amount ofacetaminophen released at this time point.

In another embodiment, release of acetaminophen and opioid from thecontrolled release component of the dosage form is achieved by erosionof the controlled release component and diffusion of the drug. In oneembodiment, release of acetaminophen from the controlled releasecomponent is achieved by erosion of one or more polymer components inthe layer to expose the acetaminophen to the external environment forrelease of the drug. In another embodiment, release of the opioid fromthe controlled release component of the dosage form is achieved byerosion of the controlled release component and diffusion of the opiodthrough a hydrated polymer layer in the controlled release component.The cumulative percent of opioid released is linear when plotted as afunction of square root of time for at least a period of 2 hours, morepreferably 4 hours.

V. METHODS OF TREATING PAIN

In another aspect, a subject suffering from pain or at risk ofexperiencing pain is treated by oral administration of a gastricretentive extended release dosage form as described above. Treatment ofboth acute pain and chronic pain are contemplated.

The method of the present invention is useful for treating numerous painstates that are currently being treated with conventional immediateformulations comprising acetaminophen and/or and opioid. These andadditional pain states include, by way of illustration and notlimitation, headache pain, pain associated with migraine, neuropathicpain selected from the group consisting of diabetic neuropathy, HIVsensory neuropathy, post-herpetic neuralgia, post-thoracotomy pain,trigeminal neuralgia, radiculopathy, neuropathic pain associated withchemotherapy, reflex sympathetic dystrophy, back pain, peripheralneuropathy, entrapment neuropathy, phantom limb pain, and complexregional pain syndrome, dental pain, pain associated with a surgicalprocedure and or other medical intervention, bone cancer pain, jointpain associated with psoriatic arthritis, osteoarthritic pain,rheumatoid arthritic pain, juvenile chronic arthritis associated pain,juvenile idiopathic arthritis associated pain, Spondyloarthropathies(such as ankylosing spondylitis (Mb Bechterew) and reactive arthritis(Reiter's syndrome)) associated pain, pain associated with psoriaticarthritis, gout pain, pain associated with pseudogout (pyrophosphatearthritis), pain associated with systemic lupus erythematosus (SLE),pain associated with systemic sclerosis (scleroderma), pain associatedwith Behcet's disease, pain associated with relapsing polychondritis,pain associated with adult Still's disease, pain associated withtransient regional osteoporosis, pain associated with neuropathicarthropathy, pain associated with sarcoidosis, arthritic pain, rheumaticpain, joint pain, osteoarthritic joint pain, rheumatoid arthritic jointpain, juvenile chronic arthritis associated joint pain, juvenileidiopathic arthritis associated joint pain, Spondyloarthropathies (suchas ankylosing spondylitis (Mb Bechterew) and reactive arthritis(Reiter's syndrome)) associated joint pain, gout joint pain, joint painassociated with pseudogout (pyrophosphate arthritis), joint painassociated with systemic lupus erythematosus (SLE), joint painassociated with systemic sclerosis (scleroderma), joint pain associatedwith Behcet's disease, joint pain associated with relapsingpolychondritis, joint pain associated with adult Still's disease, jointpain associated with transient regional osteoporosis, joint painassociated with neuropathic arthropathy, joint pain associated withsarcoidosis, arthritic joint pain, rheumatic joint pain, acute pain,acute joint pain, chronic pain, chronic joint pain, inflammatory pain,inflammatory joint pain, mechanical pain, mechanical joint pain, painassociated with the fibromyalgia syndrome (FMS), pain associated withpolymyalgia rheumatica, monarticular joint pain, polyarticular jointpain, nociceptive pain, psychogenous pain, pain of unknown etiology,pain mediated by IL-6, IL-6 soluble receptor, or IL-6 receptor, painassociated with a surgical procedure in a patient with a clinicaldiagnosis of OA, pain like static allodynia, pain like dynamicallodynia, pain associated with Crohn's disease, and/or pain associatedwith completion of a large number of patent applications within alimited interval of time.

Generally, the frequency of administration of a particular dosage formis determined to provide the most effective results in an efficientmanner without overdosing and varies according to the followingcriteria: (1) the characteristics of the particular drug(s), includingboth its pharmacological characteristics and its physicalcharacteristics, such as solubility; (2) the characteristics of theswellable matrix, such as its permeability; and (3) the relative amountsof the drug and polymer. In most cases, the dosage form is prepared suchthat effective results are achieved with administration once every eighthours, once every twelve hours, or once every twenty-four hours. Aspreviously discussed, due to the physical constraints placed on a tabletor capsule that is to be swallowed by a patient, most dosage forms canonly support a limited amount of drug within a single dosage unit.

In one embodiment, the dosage form allows a dosing frequency of twotimes a day (b.i.d.) or three times a day (t.i.d.) to result insustained plasma concentration of both drugs as compared to currentimmediate release products which require more frequent administrationfor effective sustained pain relief.

Within the context of the present disclosure, the gastric retentivedosage forms have the advantage of improving patient compliance withadministration protocols because the drugs may be administered in aonce-daily or twice-daily dosing regimen, rather than the multipledosing administrations necessary for the immediate release dosage formsof acetaminophen and/or opioids in order to maintain a desired level ofpain relief. One embodiment of the invention relates to a method ofadministering a therapeutically effective amount of a combination ofacetaminophen and an opioid to a patient in need thereof, comprisingadministering the acetaminophen and opioid or pharmaceuticallyacceptable salts thereof, in a gastric retentive dosage form once in themorning or evening in a once a day daily regime. Another embodimentcomprises administering the gastric retentive dosage form twice a day,for example once in the morning and once in the evening in a twice a daydaily dosage regime.

For all modes of administration, the gastric retentive dosage formsdescribed herein are preferably administered in the fed mode, i.e., withor just after consumption of a small meal (see U.S. Publication No.2003/0104062, herein incorporated by reference). When administered inthe evening fed mode, the gastric retentive dosage form may provide thesubject with continued relief from pain through the night and into thenext day. The gastric retentive dosage form of the present invention isable to provide pain relief for an extended period of time because thedosage form allows for both extended release of the acetaminophen andopioid and the superior absorption of the drugs in the GI tract.

In some aspects, the postprandial or fed mode can also be inducedpharmacologically, by the administration of pharmacological agents thathave an effect that is the same or similar to that of a meal. Thesefed-mode inducing agents may be administered separately or they may beincluded in the dosage form as an ingredient dispersed in the shell, inboth the shell and the core, or in an outer immediate release coating.Examples of pharmacological fed-mode inducing agents are disclosed inU.S. Pat. No. 7,405,238, entitled “Pharmacological Inducement of the FedMode for Enhanced Drug Administration to the Stomach,” inventors Markey,Shell, and Berner, the contents of which are incorporated herein byreference.

EXAMPLES

The following examples illustrate certain aspects and advantages of thesubject matter, however, the present invention is in no way consideredto be limited to the particular embodiments described below.

Example 1 Acetaminophen (APAP) and Phenylephrine (PE) CombinationFormulations

Dosage forms were made using an phenylephrine HCl (“PE”) model.Phenylephrine is highly soluble in water (500 mg/ml) with a molecularweight (203.67 Daltons (Da)). This solubility is of the same order ofmagnitude as the above mentioned opioids in a similar molecular weightrange (approximately 350 to 450 Da) with similar dose strength and doserange on a milligram basis.

Four formulations for the production of extended release 960 mg tabletscomprising acetaminophen (APAP), phenylephrine (PE) and a swellablepolymer were manufactured using a dry blend process, and hand made on aCarver Auto C Press (Fred Carver, Inc., Indiana). The formulations alsoincluded polyvinylpyrrolidone (PVP) and magnesium stearate. Informulations (samples) 3 and 4, microcrystalline cellulose (MCC) wasalso added. The dry blend process consisted of blending all theingredients in a glass jar, and compressing into a 960 mg tablet using a0.3937″×0.7086″ Modified Oval die (Natoli Engineering, St. Charles,Mo.). The parameters for the operation of the carver Auto C Press wereas follows: 3000 lbs force, 0 second dwell time (the setting on theCarver Press), and 100% pump speed. Samples 1 and 2 contain 650 mgacetaminophen and 30 mg phenylephrine. Samples 3 and 4 contain 500 mgacetaminophen and 30 mg phenylephrine. The formulations for the tabletsare set forth below in Tables 1-4:

TABLE 1 FORMULATION COMPOSITION (wt %) Sample No. APAP PE PVP PEO N-60KMg Stearate 1 67.71 3.13 3.88 24.28 1

TABLE 2 FORMULATION COMPOSITION (wt %) Sample No. APAP PE PVP PEO 1105Mg Stearate 2 67.71 3.13 3.88 24.28 1

TABLE 3 FORMULATION COMPOSITION (wt %) Sample No. APAP PE PVP PEO N-60KMCC Mg Stearate 3 52.08 3.13 3.88 24.22 16.60 1

TABLE 4 FORMULATION COMPOSITION (wt %) Sample No. APAP PE PVP PEO 1105MCC Mg Stearate 4 52.08 3.13 2.97 24.22 16.60 1

Gastric retentive acetaminophen (APAP) and phenylephrine (PE)combination 1000 mg tablets were manufactured using a dry blend process,and hand made on a Carver Auto C Press (Fred Carver, Inc., Indiana). Thedry blend process consisted of blending all the ingredients in a glassjar, and compressing into a 1000 mg tablet (650 mg APAP and 30 mg PEdose) using a 0.3937″×0.7086″ Modified Oval die (Natoli Engineering, St.Charles, Mo.). The parameters for the operation of the carver Auto CPress were as follows: 3000 lbs force, 0 second dwell time (the settingon the Carver Press), and 100% pump speed. The formulations for thetablets are set forth in Table 9:

TABLE 5 FORMULATION COMPOSITION (wt %) Sample No. APAP PE MCC PEO N-60KMg Stearate 5 65 3 0 31 1 6 0 3 65 31 1 7 65 0 3 31 1

The dissolution profiles for the above samples 1-7 were determined inUSP apparatus (40 mesh baskets), 100 rpm, in pH 5.8 phosphate buffer.Samples of 5 ml at each time-point, were taken without media replacementat 1, 2, 4, 6, 8 and 12 hours. The resulting cumulative dissolutionprofiles for samples 1-4, based upon a theoretical percent active addedto the formulations, are set forth in Tables 6 and 7 below.

TABLE 6 THEORETICAL wt % OF ACTIVE RELEASED SAMPLE 1 SAMPLE 2 TIME(HOURS) APAP PE APAP PE 1 34.0 26.5 22.1 33.6 2 42.5 39.5 32.1 46.5 453.8 56.4 46.8 64.5 8 68.4 76.2 66.8 86.4 12 79.0 87.5 80.4 97.6

TABLE 7 THEORETICAL wt % OF ACTIVE RELEASED SAMPLE 3 SAMPLE 4 TIME(HOURS) APAP PE APAP PE 1 10.9 28 11.4 33.7 2 18.3 39.5 21.4 47.7 4 31.155.3 38.5 66.3 8 66.5 87.1 79.3 97.7 12 51.5 75.3 62.6 87.3

The cumulative dissolution release profiles of formulation samples 1-4are shown in FIG. 1-FIG. 4.

The cumulative dissolution profiles for 5, 6 and 7, based upon atheoretical percent active added to the formulations is set forth inTable 8:

TABLE 8 THEORETICAL wt % OF ACTIVE RELEASED SAMPLE 5 SAMPLE 6 SAMPLE 7TIME (HOURS) APAP PE PE APAP 1 11 31.5 21.9 11.7 2 18 44.2 34.4 18.9 430 61.3 53.9 30.8 8 49 82.1 77.4 49.5 12 64.6 94 90.2 64.6

The cumulative dissolution release profiles of samples 5, 6 and 7 areshown in FIG. 5.

The disintegration was determined in USP Disintegration Tester in pH 5.8phosphate buffer. Samples, 1 ml at each time-point, were taken withoutmedia replacement at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 hours. The resultingcumulative disintegration profile, based upon a theoretical percentactive added to the formulation is set forth in Tables 7 and 8 below.

TABLE 9 THEORETICAL wt % OF ACTIVE RELEASED SAMPLE 1 SAMPLE 2 TIME(HOURS) APAP PE APAP PE 0.5 31.0 21.2 18.5 26.7 1 38.1 31.7 28.5 38.8 248.3 47.1 44.6 57.4 3 57.2 59.9 58.4 72.0 4 66.3 72.4 70.9 85.3 5 73.581.5 79.3 93.2 6 81.5 90.3 86.0 98.2 7 87.3 95.5 91.4 100.5 8 91.5 97.693.3 100.6

TABLE 10 THEORETICAL wt % OF ACTIVE RELEASED SAMPLE 3 SAMPLE 4 TIME(HOURS) APAP PE APAP PE 1 14.8 29.4 20.9 36.4 2 27.2 43.1 39.9 54.4 451.1 65.5 68.7 78.9 6 73.0 82.9 85.8 91.1 8 89.5 93.0 93.3 92.6

The disintegration release profiles of samples 1-4 are shown in FIG.6-FIG. 9.

Phenylephrine (PE) release profiles vs. square root of time (SQRT (T))in samples 1-4 are shown in FIG. 10 and FIG. 11, respectively. Thegraphs show that PE release mechanism in the samples are the mixture ofdiffusion and erosion. The PE release profiles vs. the square root oftime for samples 1 and 2 are shown in FIG. 10. The PE release profilesvs. the square root of time for samples 3 and 4 are shown in FIG. 11.

The use of the higher molecular weight polyethylene oxide N60K resultedin a slower rate of release as compared to the use of polyethylene oxide1105 (for example, compare FIG. 1 and FIG. 2 and compare FIG. 3 and FIG.4). Adding microcrystalline cellulose to the formulation having 500 mgacetaminophen and polyethylene oxide N60K resulted in a slower releaseof acetaminophen as compared to the release of phenylephrine (forexample, compare FIG. 1 and FIG. 3 and compare FIG. 6 and FIG. 8).

Example 2 Acetaminophen and Oxycodone Hydrochloride Extended ReleaseGastric Retentive Formulations

An extended release matrix comprising acetaminophen, oxycodonehydrochloride and one of two poly(ethylene oxide) polymers (POLYOX®) wasmanufactured using a fluid bed granulation process followed byscreening, blending and compression. Each formulation was prepared in abatch (lot) of 1000 g and contained 42.3 to 42.4 wt % acetaminophen, 2.3to 2.4 wt % oxycodone hydrochloride, and 1.4 wt % povidone USP(K-29/32). After the granulation, the API granules were screened throughUSP #20 mesh screen, and blended with various amount of two differentgrades of POLYOX®, microcrystalline cellulose (Avicel PH 101 NF), andMagnesium Stearate, NF. The blend was then compressed into tablets andready for analysis. Each batch varied in the amount and type of polymerpresent. Table 11 below shows the formulation of each batch with POLYOX®1105 and POLYOX® N60K. Amounts of microcrystalline cellulose (Avicel® PH101) were varied based on the amounts of the polymer.

TABLE 11 Polymer Microcrystalline Microcrystalline Lot Polymer (mg/Cellulose Cellulose Number (wt/wt %) tablet) (wt/wt %) (mg/tablet)081104- POLYOX ® 142.8 mg (32.9%;) 235.3 mg 01 1105 (20%) 081104-POLYOX ® 228.8 mg (20.9%;) 149.4 mg 02 1105 (32%) 081104- POLYOX ® 356.3mg  (3.2%;)  23.1 mg 03 1105 (50%) 081104- POLYOX ®  72.0 mg (42.9%;)306.5 mg 04 N60K (10%) 081104- POLYOX ® 229.0 mg (20.9%;) 149.4 mg 05N60K (32%) 081104- POLYOX ® 322.0 mg  (7.9%;)  56.4 mg 06 N60K (45%)

Batches (lots) of 1 kg each were prepared for each formulation. For eachformulation, the acetaminophen was sprayed with a 8.0-8.5% weight/weightsolution of povidone and oxycodone hydrochloride in water in a fluid bedgranulator (GLATT® top spray GPCG1). Fluid bed process parametersincluding spray rate (10-30 g/ml), inlet air temperature (50-70° C.),and fluidized air volume were varied to maintain the granule producttemperature at a range of 28-35° C. Atomization air pressure wasmaintained at 1.5 bar for the entire granulation process. Granules weredried and blended with the polymer, filler and lubricant using aV-blender (PK blender, Patterson-Kelly Harsco). The polymer and fillerwere first blended for 10-15 minutes, the lubricant was then added, andblending was continued for another 4 minutes.

Tablets were then prepared using a Manesty® Beta press, tooled with amodified oval 0.3937″ width×0.6299″ length×0.075″ cup depth die. Acompression force of 7-13 kN (kilo Newton) was used, with a speed of1000-2200 tablets/min.

Disintegration profiles for the tablets produced from the six batchesdescribed above were determined in USP Disintegration Tester in pH 1.2,0.1 N HCl at 37±2° C. Samples were taken without media replacement at 1,2, 4, 6, 7 and 8 hours.

Results of the disintegration tests for the tablets having theformulations set forth in Table 11 are presented in Table 12 (cumulativeoxycodone hydrochloride release) and 13 (cumulative acetaminophenrelease). Graphical representation of the data is provided in FIG.12-FIG. 13.

TABLE 12 (Cumulative Oxycodone Hydrochloride Release) Lot Lot Time081104- 081104- Lot Lot Lot Lot (hr) 01 02 081104-03 081104-04 081104-05081104-06 1 55 31 25 67 26 22 2 72 51 43 84 40 36 3 98 85 76 103 67 61 6111 106 104 — 94 88 7 — — 106 — 100 96 8 — — — — 106 105

TABLE 13 (Cumulative Acetaminophen Release) Lot Lot Time 081104- 081104-Lot Lot Lot Lot (hr) 01 02 081104-03 081104-04 081104-05 081104-06 1 5024 17 63 18 14 2 68 45 35 81 32 27 3 96 80 71 107 60 52 6 114 107 106 —90 81 7 — 108 110 — 98 92 8 — — — — 106 104

The results clearly show that release depends at least in part upon themolecular weight of the poly(ethylene oxide) polymer, the percentcomposition of the polymer, and the amount of microcrystalline cellulosein the formulation. The cumulative release of oxycodone hydrochloride ispresented in FIG. 12, which shows that approximately 20-55% of theoxycodone hydrochloride was released from the tablets containing POLYOX®1105 within the first hour. The cumulative release profiles of oxycodonehydrochloride from tablets having POLYOX® N60K, shows that approximately20-65% of the oxycodone hydrochloride was released from the tabletswithin the first hour. Extended release approaching zero-order wasobserved over a period of approximately 6 hours for the tabletscontaining POLYOX® 1105, while tablets containing 32% or 45% POLYOX®N60K exhibited approximately zero-order release over a period ofapproximately 8 hours.

The acetaminophen cumulative release profiles for the same dosage formsare presented in FIG. 13, which shows that a range of approximately20-50% of the acetaminophen was released from the tablets containingPOLYOX® 1105 in the first hour, while the cumulative release profiles ofacetaminophen from tablets having POLYOX® N60K, show that approximately15-65% of the acetaminophen was released from the tablets within thefirst hour. The tablets containing 32% or 45% POLYOX® N60K exhibitedextended release approaching zero-order over a period of approximately 8hours, as seen with the oxycodone hydrochloride.

Linear regression of data presented in FIG. 12-13 was performed for lots08110403 (50% POLYOX® 1105) and 08110406 (45% POLYOX® N60K) as shown inFIG. 14 and FIG. 15, respectively. It was determined that oxycodonehydrochloride was released from the tablets having 50% POLYOX® 1105 at alinear rate of approximately 2.8 mg/h while the acetaminophen wasreleased at a rate of approximately 48 mg/h.

Linear regression of cumulative release data for lot 08110406 (45%POLYOX® N60K) show that oxycodone hydrochloride was released from thetablets at a linear rate of approximately 2.1 mg/h while theacetaminophen was released at a rate of approximately 36.8 mg/h.

Content uniformity analysis of lots 08110403 and 08110406 was done byanalyzing five tablets from each batch. Each tablet was weighed thentransferred to a 250 mL volumetric flask to which 200 mL 0.1 N HCl wasadded. The flask was then set on a magnetic stirrer, a magnetic stir barwas put into the flash and the solution was stirred at approximately1000 rpm overnight at room temperature, until all fragments had visiblydissolved. Additional 0.1 N HCl was then added to the flask to a finalvolume of 250 mL and stirred for an additional 30 minutes. One mL ofeach solution for each tablet was placed into a separate flask anddiluted with mobile phase solution (97% water/3% IPA/0.1% TFA, apparentpH=3.0±0.1) for analysis on a Agilent 1100/1200 HPLC system.

The resultant data are shown in Tables 14 and 15, respectively. Fortablets containing 50% POLYOX® 1105, content uniformity with respect tooxycodone hydrochloride ranged from 91.0% to 92.4% of the label claim,with a mean of 91.6% and a standard deviation of 0.7. Content uniformitywith respect to the acetaminophen ranged from 98.5% to 100.5% of thelabel claim with a mean of 99.4% and a standard deviation of 0.9.

For tablets containing 45% POLYOX® N60K, content uniformity with respectto oxycodone hydrochloride ranged from 91.0% to 95.2% of the labelclaim, with a mean of 91.6% and a standard deviation of 0.7. Contentuniformity with respect to the acetaminophen ranged from 99.2% to 103.1%of the label claim with a mean of 99.4% and a standard deviation of 0.9.

TABLE 14 (Content Uniformity for Oxycodone Hydrochloride) APAP % LC OXY% LC Lot Number (304 mg) (16 mg) 08110403-1 100.5 92.4 08110403-2 98.891.2 08110403-3 98.5 91.0 08110403-4 100.2 92.3 08110405-5 99.1 91.2Mean 99.4 91.6 Stnd Dev 0.9 0.7 % RSD 0.9 0.7

TABLE 15 (Content Uniformity for Acetaminophen) APAP % LC OXY % LC LotNumber (304 mg) (16 mg) 08110406-1 99.2 91.0 08110406-2 101.9 93.608110406-3 103.1 95.2 08110406-4 101.5 93.4 08110406-5 99.9 91.9 Mean101.1 93.0 Stnd Dev 1.6 1.6 % RSD 1.5 1.8

Tablets were tested for hardness using a Venkel Tablet Tester accordingto standard USP protocol. Tablet hardness ranged from 9-12 kp.

Example 3

An immediate release composition having acetaminophen and oxycodonehydrochloride was produced using the methods described herein. Theformulation is presented in Table 16 below.

TABLE 16 Ingredient % wt/wt Mg/Tablet Acetaminophen 71.3 233.2 mgOxycodone hydrochloride 4.9 16.0 mg Povidone, NF (Plasdone, 9.2 30.1K29/32) Croscarmellose Sodium, 1.7 5.6 NF (Ac-Di-Sol) LactoseMonohydrate, NF 6.0 19.6 (316 Fast Flow) Microcrystalline Cellulose, 6.019.6 NF (Avicel PH-101) Magnesium Stearate NF 0.9 2.9 (Non-bovine) Totalweight 327.0

A mixture containing the acetaminophen, croscarmellose sodium, lactosemonohydrate, and microcrystalline cellulose was sprayed with a solutioncontaining the oxycodone hydrochloride and povidone (approximately 9%)in water in a fluid bed granulator (Vector® top spray FLM1). Thegranules were then screened through a USP #20 mesh screen. The resultantgranules were blended with magnesium stearate in a V-blender (PKblender, Patterson-Kelly Harsco) for 4 minutes, and were then ready forbilayer compression.

Example 4

Bilayer tablets containing the extended release polymer matrix and theimmediate release component (Example 3) were prepared using a Manesty®BB4 press, tooled with a modified oval 0.4337″ width×0.7450″ length die.The formulation for the extended release material used in thecompression is presented in Table 17 below.

TABLE 17 Ingredient % wt/wt Mg/Tablet Acetaminophen 41.9 300.0 mgOxycodone hydrochloride 2.6 18.8 mg Polyethylene oxide, NF 45.0 321.8(SENTRY ™ POLYOXY ™ WSR N 60K, LEO) Povidone, NF (Plasdone, 3.5 25.0K29/32) Microcrystalline Cellulose, 6.0 43.0 NF (Avicel PH-101)Magnesium Stearate NF 1.0 7.2 (Non-bovine) Total weight 715.0

The bilayer tablets were then characterized with respect to cumulativedrug release using the USP Disintegration test at 37±2° C. in 0.1N HCl.Results, presented in Table 18 and illustrated in FIG. 16, show thatapproximately 50-55% of the acetaminophen had been released at the firsttime point of 1 hour, while approximately 55-57% of the oxycodonehydrochloride had been released by this time. This is indicative of drugrelease by the immediate release layer. Proportional release ofacetaminophen and oxycodone hydrochloride was observed over a period of8 hours.

TABLE 18 Time Point Cumulative Acetaminophen Cumulative Oxycodone(hours) Released (%) Hydrochloride Released (%) 1 53.2 57.2 2 62.6 67.04 77.6 83.0 6 88.2 95.8 7 92.7 100.9 8 96.1 105.1

The bilayer tablets were further characterized with respect to contentuniformity. Five tablets were analyzed and the results, presented inTable 19, show that content uniformity ranged from 121.8 to 125.2% ofthe label claim for acetaminophen and ranged from 110.5 to 113.5% foroxycodone HCl. The standard deviation of the acetaminophen and oxycodoneHCl were each 1.3, demonstrating that there is very little variationamong the tablets with respect to the milligrams of acetaminophen andoxycodone HCl present in the tablets.

TABLE 19 C.U. Results APAP % LC Oxy % LC 1 124.5 113.0 2 121.8 110.5 3125.2 113.5 4 123.7 111.5 5 123.0 111.1 Ave. 123.6 111.9 Std. Dev. 1.31.3 % RSD 1.1 1.1

Example 5

Bilayer tablets were also prepared using a high shear granulationmethod. A 5 kg batch was prepared for the gastric retentive extendedrelease mixture and for the immediate release component mixture. Theextended release layer contained 42.9% acetaminophen, 2.4 wt % oxycodonehydrochloride, 2.7 wt % povidone, 45.0 wt % POLYOX® N60K, 6.0 wt %microcrystalline cellulose, and 1.0 wt % magnesium stearate. Theimmediate release layer contained 77.5 wt % acetaminophen, 5.2 wt %oxycodone hydrochloride, 4.0 wt % povidone, 3.0 wt % croscarmellosesodium, 9.2 wt % microcrystalline cellulose, and 0.9 wt % magnesiumstearate.

Granules for the extended release layer were prepared by high sheargranulation using water as the granulating liquid. The acetaminophen,oxycodone hydrochloride and povidone were charged into a bench scalehigh shear granulator (Glatt®). The dry powders were blended by runningthe blade for 1 minute, after which time the water was sprayed onto themixing blend at a spray rate of approximately 5-30 gm/min. Afterinitiating the spray, the chopper was started and run throughout thespray. Once the granulation was complete, the granulation was dischargedfrom the high shear granulator, and dried using a fluid bed processor(Glatt® top spray GPCG1). Dry granules were screened through an 20-meshUSP screen. Screened granules were blended with the remaining excipientsexcept magnesium stearate in a V-blender (PK blender, Patterson-KellyHarsco) for 15 minutes. The magnesium stearate was then added to themixture and blended for another 4 minutes, and ready for bi-layercompression.

Granules for the immediate release layer were prepared using the highshear method as described above for the extended release layer. Theacetaminophen, oxycodone hydrochloride, povidone, croscarmellose sodium,and microcrystalline cellulose were granulated using the high shearmethod prior to blending with magnesium stearate. Granules were screenedthrough USP #20-mesh screen before blending with magnesium stearate.After blending, they were ready for bi-layer compression.

The extended release and immediate release blends were compressed intobilayer tablets using a hand roll method with a Manesty® Beta BB4 press,tooled with a modified oval 0.4337″ width×0.7450″ length die.

The bilayer tablets prepared by high shear granulation werecharacterized with respect to cumulative drug release using the USPDisintegration test at 37±2° C. in 0.1 N HCl. Results are presented inFIG. 17 and show that approximately 50% of the acetaminophen had beenreleased at the first time point of 1 hour, while approximately 50% ofthe oxycodone HCl had been released by this time. This is indicative ofdrug release by the immediate release layer. Proportional release ofacetaminophen and oxycodone HCl was observed over a period ofapproximately 8 hours.

The bilayer tablets were further characterized with respect to contentuniformity. Five tablets were analyzed and the results, presented inTable 20, show that content uniformity ranged from 99.1% to 101.9% ofthe label claim for acetaminophen and ranged from 98.6% to 101.4% foroxycodone HCl. The standard deviation for acetaminophen and oxycodoneHCl was 1.2 and 1.3, respectively. Both values demonstrate very lowlevels of variability among individual tablets with respect to themilligrams of acetaminophen and oxycodone HCl present in the tablets.

Machine production of the bilayer tablets using the Manesty® Beta BB4press tooled with a modified oval 0.4337″ width×0.7450″ length dieresulted in tablets in which the IR layer was subject to capping.

TABLE 20 C.U. Results APAP % LC Oxy % LC 1 99.1 99.2 2 99.2 98.6 3 101.1101.4 4 101.9 101.4 5 99.1 98.6 Ave. 100.1 99.8 Std. Dev. 1.2 1.3 % RSD1.2 1.3

Example 6

An extended release matrix comprising acetaminophen, tramadolhydrochloride and 45% POLYOX® N60K was manufactured using a fluid bedgranulation process followed by screening, blending and compression asdescribed in Example 2. The formulation is shown in Table 21 below:

TABLE 21 Ingredients % w/w mg/tablet APAP, USP 41.9 299.9 PowderTramadol HCl 2.6 18.8 Povidone, USP 3.4 24.5 (K-29/32) POLYOX, NF 45.0321.8 (N60K) Avicel, NF 6.0 43.0 (PH 101) Mg Stearate, NF 1.0 7.2 Totaltablet weight 715 mg

Fluidized bed granulation was performed on Vector FL-M-1 Fluid BedGranulator. The acetaminophen was sprayed with a binder solutioncontaining the PVP and the tramadol hydrochloride. After granulation,the resultant preparation was characterized with respect to final losson drying (LOD), bulk density, and tap density.

The granulation parameters and post-granulation characterization arepresented below in Table 22.

TABLE 22 09011201 09012001 09012101 09012201 09012202 Granulation Batchsize (g) 1000 1000 1000 1000 1000 Inlet air temp (° C.) 56 53-56 52-5650-58 51-58 Product temp at spray start 30 32 31 30 31 (° C.) Producttemp during spray (° C.) 30-38 31-34 30-34 30-36 30-34 Spray rate (rpm)15-20 12-20 12-20 12-20 12-20 Spraying time (min) 29 23 22 23 24 Producttemp during drying (° C.) 36-42 34 34-35 37-38 37-38 Drying time (min) 31 1 1 1 Post-gran Final LOD (%) 1.47 1.66 1.69 1.38 1.75 Bulk Density(g/ml) 0.35 0.30 0.30 0.33 0.31 Tap Density (g/ml) 0.41 0.37 0.37 0.400.39

The granulation mixture was then screened and blended with the remainingexcipients in a V blender and compressed into tablets.

The particle size distribution of the blend was determined using aparticle size shaker with a timer (W.S. Tyler Inc., ROTAP, RX-29) andU.S. standard sieve series: No. 60 (250 um), 100 (150 um), 140 (106 um),200 (75 um), 270 (53 um) and 325 (45 um). Fifty grams of sample wasaccurately weighed and transferred to the top sieve, then the shaker wasallowed to shake for 5 minutes. The material remaining on the top ofeach sieve was then weighed to the nearest 0.1 gram. The results areprovided in Table 23 below and shown in FIG. 18.

TABLE 23 Sieve size Lot Lot Lot Lot Lot (μm) 09011201 09012001 0901210109012201 09012202 250 57.0 61.4 57.4 53.9 60.0 150 30.0 21.7 23.6 26.421.0 106 8.0 7.6 11.0 9.3 8.0 75 3.0 4.2 4.8 4.8 5.0 53 2.0 3.0 3.2 5.45.0 44 0 1.2 1.2 0.2 0 Fines 0.6 0.8 0.8 0.0 0

An immediate release matrix comprising acetaminophen and tramadol wasthen produced having the formulation presented in Table 24.

TABLE 24 Ingredients % wt/wt Acetaminophen USP Powder 0.30 Tramadol HCl4.80 Povidone USP (K-29/32) 9.00 AcDiSol 3.00 Lactose 6.45 Avicel PH1016.45

Fluidized bed granulation was performed on Vector FL-M-1 Fluid Bed asdescribed for the gastric retentive matrix. A binder solution ofpovidone and the tramadol was sprayed onto the acetaminophen. Thegranules were then blended with the remaining excipients. Thegranulation properties and the post-granulation characterization of theIR matrix are presented below in Table 25.

TABLE 25 09010502 09010901 09010902 09011301 09011502 09011503 Batchsize (g) 600 1000 1000 1000 1000 1000 Inlet air (° C.) 50-51 49-51 51-5851-58 49-53 47-49 Product temp at spray start (° C.) 35 31 36 35 31 30Product temp during spray (° C.) 32-38 28-31 33-38 33-36 29-35 29-32Spray rate (rpm)  7-15  8-19  8-20  8-19  8-19  8-19 Spraying time (min)22 25 37 36 37 37 Product temp during drying (° C.) 32-40 41 36-39 35-3734-35 32-34 Drying time (min) 3 5 2 2 2 2 Final LOD (%) 1.8 1.03 1.431.6 1.95 2.19 Bulk Density (g/ml) N/M 0.39 0.29 0.32 0.32 0.31 TapDensity (g/ml) N/M 0.45 0.34 0.38 0.40 0.38 Carr Index N/M 15 16 16 2018

Compression of the gastric retentive extended release matrix with theimmediate release matrix produced above was done using a Manesty® BB4press, at a compression speed of 220 tablets per minute, tooled with amodified oval 0.4337″ width×0.7450″ length die.

A comparison of segments of data from a 12 minute run of the tabletpress showed that the resultant tablets had a friability ranging from0.01 to 0.12 and did not split during hardness testing. The comparisondata are summarized in Table 26 below.

TABLE 26 Section Beginning Middle End Compression Compression speed(rpm) 32 32 32 Avg tablet weight (g) 1.019 ± 0.018 1.012 ± 0.016 0.992 ±0.033 Avg tablet hardness (kp) 19.6 ± 1.1  18.9 ± 1.4  17.2 ± 2.5 2^(nd) compression force (N) 9.8 11.7 9.1 Avg tablet thickness (mm) 7.8 + 0.03  7.8 ± 0.03  7.8 + 0.04 Tablets split during 0 0 0 hardnesstesting (%) Friability (%) 0.12 0.03 0.01 Samples from Samples fromSamples from bag 1/6 bag 4/6 bag 6/6

Example 7

A bilayer tablet with first and second doses of acetaminophen andtramadol, comprising a gastric retained extended release layer and animmediate release layer, and having a total weight of 1042 mg, was madeaccording to the formulations presented in Table 27 (extended release)and Table 28 (immediate release). To prepare the extended release layer,methods described in Example 2 were used. The acetaminophen, thetramadol and the binder were first wet granulated using the fluid bedgranulation described in Example 2. The resultant granulation mixturewas then screened and blended with the polymer, filler, color agent, andlubricant in a V-blender.

To prepare the immediate release layer, methods described in Example 3were used. All ingredients except magnesium stearate were wet granulatedusing the fluid bed granulation method, the granules were then screenedand blended with lubricant in a V-blender then ready for compression.

The extended release component and the immediate release component wasthen compressed into a bilayer tablet using a Manesty BB4 press, tooledwith a modified oval 0.4337″ width×0.7450″ length die. A compressionforce of 7-13 kN (kilo Newton) was used, with a speed of 1000-2200tablets/min.

TABLE 27 Ingredient Function wt % Mg/tablet Acetaminophen active agent41.9 299.9 Oxycodone active agent 2.6 18.8 Hydrochloride Povidone, NFbinder 3.4 17 (Plasdone, K29/32) Polyethylene oxide, swellable and 45.0321.8 NF (Sentry ™ release-controlling POLYOX ™ WSR polymer N60K, LEOMicrocrystalline Filler 5.8 41.5 cellulose, NF (Avicel PH-101) Opadry ®blue color agent 0.2 1.5 Magnesium lubricant 1.0 7.2 stearate, NF (non-bovine) Total 100.0 715.0

TABLE 28 Ingredient Function wt % Mg/tablet Acetaminophen active agent70.1 229.3 Oxycodone active agent 4.8 15.7 Hydrochloride Povidone, NFbinder 9.0 29.4 (Plasdone, K29/32) Croscarmellose disintegrant 3.0 9.8sodium, NF (Ac-Di- Sol) Microcrystalline Filler 6.4 21.0 cellulose, NF(Avicel PH-101) Lactose Compression-aid 6.4 21.0 monohydrate, NF (316Fast Flow) Magnesium lubricant 0.3 0.8 stearate, NF (non- bovine) Total100.0 327.0

Disintegration profiles for the tablets produced from the six batchesdescribed above were determined in USP Disintegration Tester in pH 1.20.1 N HCl at 37±2° C. Samples were taken without media replacement at 1,2, 4, 6, 7 and 8 hours. Cumulative release values for acetaminophen andtramadol at the time points are presented in Table 29 below, andillustrated in the graph in FIG. 20. The data show proportional releaserates for the acetaminophen and tramadol over a period of 7 hours.

TABLE 29 Active Ingredient 1 h 2 h 4 h 6 h 7 h 8 h Acetaminophen 51.461.6 81.0 98.3 106.5 103.5 Tramadol 59.8 72.3 95.3 112.8 118.3 122.1

Content uniformity of the bilayer tablets was tested using the methodsdescribed in Example 2. As shown in Table 30 below, the average contentuniformity based on weight for acetaminophen was 95.5% of the labelclaim, while the average content uniformity based on weight for tramadolwas 101.0% of the label claim. Standard deviations for acetaminophen andtramadol were 3.1 and 4.1, respectively.

TABLE 30 APAP, TRAM, APAP, TRAM, % LC % LC % LC % LC (base (base Tablet(522.9 mg) (37.7 mg) on wt) on wt) 1 91.5 95.6 93.8 98.5 2 92.8 97.295.9 101.0 3 93.4 98.2 96.1 101.6 4 88.9 93.3 92.1 97.1 5 90.8 94.0 91.394.9 6 92.7 96.8 94.9 99.7 7 93.2 97.7 94.5 99.7 8 92.6 98.0 96.0 102.19 95.2 102.0 101.5 109.2 10 90.3 93.2 90.7 94.1 11 92.8 98.5 97.0 103.512 94.3 99.7 97.8 103.9 13 87.3 91.5 89.9 94.7 14 92.0 99.0 99.0 107.115 90.0 93.1 91.3 95.0 16 91.4 96.5 94.1 99.9 17 88.8 91.8 89.6 93.2 1892.5 97.8 97.4 103.5 19 92.3 98.5 98.7 105.9 20 94.6 100.7 99.2 106.1 2194.1 99.7 98.5 105.0 22 94.5 100.2 98.3 104.8 23 93.3 98.4 96.0 101.8 2497.2 101.9 100.3 105.8 25 90.6 95.6 95.5 101.4 26 91.1 95.2 93.7 98.5 2791.0 95.3 94.8 99.9 28 91.7 96.8 96.2 102.0 29 92.5 97.0 95.7 100.9 3092.3 96.5 94.9 99.7 Ave. 92.2 97.0 95.5 101.0 Std. Dev. 2.1 2.8 3.1 4.1% RSD 2.2 2.9 3.2 4.1

Example 8

A bilayer tablet comprising a gastric retained extended release layerand an immediate release layer is made containing the formulationpresented in Table 31, in which the immediate release layer containedhydroxypropylcellulose (HPC) as the binder instead of PVP. The extendedrelease layer contains PVP as the binder and was prepared as describedin Example 2. The acetaminophen, the opioid and povidone (PVP) werefirst wet granulated using the fluid bed. The resultant granulationmixture was then blended with the polymer, filler, and lubricant in aV-blender. To prepare the immediate release layer, the acetaminophen,the opioid, and hydroxypropylcellulose (HPC) were first wet granulatedusing the fluid bed granulation. The resultant granulation mixture wasthen blended with the lubricant. The bilayer tablets were compressed ona Manesty BB4 machine using 0.4330″ wide×0.7450 long modified ovaltooling. The amounts of each component in the bilayer tablets ispresented in Table 31. The dissolution release profile of acetaminophenand oxycodone HCl is shown in Table 32 and in FIG. 21 and FIG. 22.

TABLE 31 Ingredient Function wt % Mg/tablet Acetaminophen active agent50.88 500 Oxycodone active agent 3.05 30 Hydrochloride Hydroxypropylbinder 2.88 28 cellulose, NF (Klucel EF) Polyethylene Oxide, Swellableand 28.73 282 NF (Sentry ™ release-controlling POLYOX ™ WSR polymerN60K, LEO Povidone, NF binder 1.53 15 (Plasdone, K29/32) Croscarmellosedisintegrant 1.08 11 sodium, NF (Ac-Di- Sol) Microcrystalline Filler7.75 76 cellulose, NF (Avicel PH-101) Lactose Compression-aid 3.60 35monohydrate, NF (316 Fast Flow) Magnesium lubricant 0.50 5 stearate, NF(non- bovine) Total 100.0 982.0

TABLE 32 N = 6 TIME (HOURS) APAP Oxycodone 0.5 51.34154 53.25 1 54.8392658.64767 2 60.27355 66.0131 4 69.5474 76.92073 6 77.73934 85.02003 884.23556 90.55967 12 93.07368 95.14833 13 94.74338 95.73057

Example 9

A bilayer tablet comprising a gastric retained extended release layerand an immediate release layer, having a total weight of 1042 mg, ismade according to the formulations presented in Table 33 (extendedrelease) and Table 34 (immediate release). To prepare the extendedrelease layer, methods described in Example 2 are used. Theacetaminophen, the opioid and the binder are first wet granulated usingthe fluid bed granulation described in Example 2. The resultantgranulation mixture is then screened and blended with the polymer,filler, color agent, and lubricant in a V-blender.

To prepare the immediate release layer, methods described in Example 3are used. All ingredients except magnesium stearate are wet granulatedusing the fluid bed granulation method, the granules are then screenedand blended with lubricant in a V-blender then ready for compression.

The extended release component and the immediate release component arethen compressed into a bilayer tablet using a Carver press, tooled witha modified oval 0.4850″ width×0.7450″ length modified Oval die. Acompression force of 7-13 kN (kilo Newton) was used, with a speed of1000-2200 tablets/min.

TABLE 33 Ingredient Function wt % Mg/tablet Acetaminophen active agent41.9 299.9 Oxycodone active agent 2.6 18.8 Hydrochloride Povidone, NFbinder 3.4 17 (Plasdone, K29/32) Polyethylene oxide, swellable and 45.0321.8 NF (Sentry ™ release-controlling POLYOX ™ WSR polymer N60K, LEOMicrocrystalline Filler 5.8 41.5 cellulose, NF (Avicel PH-101) Opadry ®blue color agent 0.2 1.5 Magnesium lubricant 1.0 7.2 stearate, NF (non-bovine) Total 100.0 715.0

TABLE 34 Ingredient Function wt % Mg/tablet Acetaminophen active agent70.1 229.3 Oxycodone active agent 4.8 15.7 Hydrochloride Povidone, NFbinder 9.0 29.4 (Plasdone, K29/32) Croscarmellose disintegrant 3.0 9.8sodium, NF (Ac-Di- Sol) Microcrystalline Filler 6.4 21.0 cellulose, NF(Avicel PH-101) Lactose Compression-aid 6.4 21.0 monohydrate, NF (316Fast Flow) Magnesium lubricant 0.3 0.8 stearate, NF (non- bovine) Total100.0 327.0

Example 10

A bilayer tablet containing a total of 500 mg acetaminophen and 15 mgoxycodone HCl designed for release of these active agents over 8 hourswas manufactured using the wet granulation methods as described aboveusing the formulations presented in Tables 35 and 36 for the ER and IRlayers, respectively.

The extended release component and the immediate release component arethen compressed into a bilayer tablet using a Manesty BB4 press, tooledwith a modified oval 0.4337″ width×0.7450″ length die. A compressionforce of 1500 pounds was used, with a speed of 100% with a dwell time of0.

TABLE 35 wt % mg/tablet Acetaminophen 42.5 304.0 Oxycodone HCl 1.1 8.0Povidone, NF (Plasdone, 3.4 24.5 K29/32) Polyethylene oxide, 301 NF 45.0321.8 LEO Microcrystalline Cellulose, 3.9 28.1 NF (Avicel PH-101)Opadry ® blue 3.0 21.5 Magnesium Stearate, NF 1.0 7.2 (Non-Bovine) Total100.0 715.0

TABLE 36 wt % mg/tablet Acetaminophen 68.8 196.0 Oxycodone HCl 2.5 7.0Povidone, USP (K29/32) 10.3 29.4 Ac-Di-Sol 3.4 9.8 Lactose 7.4 21.0Avicel PH-101 7.4 21.0 Magnesium Stearate, NF 0.3 0.7 Total 100.0 284.9

The disintegration release profile of acetaminophen and oxycodone HClformulated for acetaminophen and oxycodone release over 8 hours isprovided in Table 37 and illustrated in FIG. 23.

TABLE 37 Time Point (h) 1 2 4 6 7 8 Cumulative % 49.4 56.3 70.1 77.580.1 85.2 APAP released Std. Dev. 0.7 1.3 6.1 2.3 2.3 3.5 Cumulative %61.1 69.1 79.8 86.0 87.2 89.8 Oxy released Std. Dev. 1.2 1.4 1.8 1.9 2.12.3

Example 11

A bilayer tablet containing a total of 500 mg acetaminophen and 15 mgoxycodone HCl formulated for release of the active pharmaceuticalingredients over 6 hours was manufactured as described above using theformulations presented in Tables 38 and 39 for the ER and IR layers,respectively.

TABLE 38 wt % mg/tablet Acetaminophen 37.8 270.0 Oxycodone HCl 1.1 8.0Povidone, NF (Plasdone, 3.4 24.5 K29/32) Polyethylene oxide, 301 NF 45.0321.8 LEO Microcrystalline Cellulose, 8.7 62.1 NF (Avicel PH-101)Opadry ® blue 3.0 21.5 Magnesium Stearate, NF 1.0 7.2 (Non-Bovine) Total100.0 715.0

TABLE 39 wt % mg/tablet Acetaminophen 72.1 230.0 Oxycodone HCl 2.2 7.0Povidone, USP (K29/32) 9.2 29.4 Ac-Di-Sol 3.1 9.8 Lactose 6.6 21.0Avicel PH-101 6.6 21.0 Magnesium Stearate, NF 0.3 0.8 Total 100.0 319.0

The disintegration release profile of acetaminophen and oxycodone HClfrom the tablet formulation for release over 6 hours is provided inTable 40 and illustrated in FIG. 24.

TABLE 40 Time Point (h) 1 2 4 6 7 8 Cumulative % 60.2 69.3 83.1 91.793.5 95.8 APAP released Std. Dev. 1.3 2.1 2.2 1.6 1.5 1.3 Cumulative %63.8 73.8 86.8 93.7 94.5 96.6 Oxy released Std. Dev. 1.4 3.3 2.3 1.8 2.82.5

Example 12

A bilayer tablet containing a total of 500 mg acetaminophen and 30 mgoxycodone HCl designed for release over 8 hours was manufactured usingthe wet granulation methods as described above using the formulationspresented in Tables 41 and 42 for the ER and IR layers, respectively.

The extended release component and the immediate release component arethen compressed into a bilayer tablet using a Manesty BB4 press, tooledwith a modified oval 0.4337″ width×0.7450″ length die. A compressionforce of 7-13 kN (kilo Newton) was used, with a speed of 1000-2200tablets/min.

TABLE 41 wt % mg/tablet Acetaminophen 42.5 304.0 Oxycodone HCl 2.2 16.0Povidone, NF (Plasdone, 3.4 24.6 K29/32) Polyethylene oxide, 301 NF 45.0321.8 LEO Microcrystalline Cellulose, 2.8 20.0 NF (Avicel PH-101)Opadry ® blue 3.0 21.5 Magnesium Stearate, NF 1.0 7.2 (Non-Bovine) Total100.0 715.0

TABLE 42 wt % mg/tablet Acetaminophen 67.1 196.0 Oxycodone HCl 4.8 7.0Povidone, USP (K29/32) 10.1 29.4 Ac-Di-Sol 3.4 9.8 Lactose 7.2 21.0Avicel PH-101 7.2 21.0 Magnesium Stearate, NF 0.25 0.7 Total 100.0 291.9

The disintegration release profile of acetaminophen and oxycodone HClformulated for acetaminophen and oxycodone release over 8 hours isprovided in Table 43 and illustrated in FIG. 25.

TABLE 43 Time Point (h) 1 2 4 6 7 8 Cumulative % 52.4 59.3 73.7 79.682.8 85.5 APAP released Std. Dev. 1.3 2.2 5.3 5.1 5.7 6.5 Cumulative %69.9 75.3 84.1 89.9 91.2 93.0 Oxy released Std. Dev. 10.5 5.5 6.7 7.68.1 8.7

Example 13

A bilayer tablet containing a total of 500 mg acetaminophen and 30 mgoxycodone HCl formulated for release of the active pharmaceuticalingredients over 6 hours was manufactured as described above using theformulations presented in Tables 44 and 45 for the ER and IR layers,respectively.

TABLE 44 wt % mg/tablet Acetaminophen 37.8 270.0 Oxycodone HCl 2.2 16.0Povidone, NF (Plasdone, 3.1 22.0 K29/32) Polyethylene oxide, 301 NF 45.0321.8 LEO Microcrystalline Cellulose, 7.9 56.7 NF (Avicel PH-101)Opadry ® blue 3.0 21.5 Magnesium Stearate, NF 1.0 7.2 (Non-Bovine) Total100.0 715.0

TABLE 45 wt % mg/tablet Acetaminophen 70.6 230.0 Oxycodone HCl 4.3 14.0Povidone, USP (K29/32) 9.0 29.4 Ac-Di-Sol 3.0 9.8 Lactose 6.4 21.0Avicel PH-101 6.4 21.0 Magnesium Stearate, NF 0.3 0.8 Total 100.0 326.0

The disintegration release profile of acetaminophen and oxycodone HClfrom the tablet formulation for release over 6 hours is provided inTable 46 and illustrated in FIG. 26. The release profiles indicate thatboth acetaminophen and oxycodone exhibit approximately zero-orderrelease kinetics over about a 6 to 8 hour period. In vivo erosionstudies of the dosage forms to demonstrate gastric retention of thetables are described in Examples 17-18.

TABLE 46 Time Point (h) 1 2 4 6 7 8 Cumulative % 59.2 67.9 80.9 90.294.4 95.0 APAP released Std. Dev. 1.0 1.7 1.8 1.8 1.9 1.9 Cumulative %69.7 79.8 93.3 101.0 104.7 104.4 Oxy released Std. Dev. 1.4 2.1 2.1 2.64.1 2.1

Example 13

Studies were done to evaluate the effect of the binder on thedegradation rate of oxycodone in the presence of polyethylene oxide inthe ER portion of the dosage form. Specifically, the use of HPC or PVP.Oxycodone HCl as well as a physical blend of acetaminophen and oxycodoneHCl were tested (“Physical Blend”). Single layer ER tablets containingacetaminophen (APAP) and oxycodone HCl (Oxy) were formulated using thefluid bed granulation method described above. Specifically, theacetaminophen and oxycodone were granulated in the presence of eitherHPC or PVP as the binder. Granulated mixtures were then dried andpressed into tablets. Physical blends and tablets were then stored at40° C., 75% relative humidity (RH) in an open dish for 8 days. Physicalblends and tablets were analyzed for the presence of an unknown impurityand the ratio of the unknown purity to oxycodone (Oxy) was calculated.Physical blend and granules data are listed as an average of threeindividual sample preparations. Tablet data were obtained by analyzingone composite sample from five tablets.

The results are summarized in Table 47 and show that oxycodone HCl wasmore stable in tablets formulated with HPC as compared to PVP as thebinder and suggest that it may be beneficial to formulate both the IRand ER layers of the dosage form using HPC rather than PVP as thebinder.

TABLE 47 DHOXY/OXY (%)¹ Physical Blend⁴ Tablets⁵ 40° C., 75% RH,Granules⁴ 40° C., 75% RH, Physical Blend Polyox t = 0 open-dish 8 days t= 0 t = 0 open-dish 8 days Oxy only NA 0.07 0.07 NA NA NA APAP (500 mg)/NA 0.02 0.10 NA NA NA Oxy (30 mg) APAP/Oxy as a ER Single Layer APAP(304 mg) N60K 1.35 1.41 1.49 Oxy (16 mg) PVP (24.6 mg) NA NA 301 NA NA1.23 1.47 APAP (304 mg) N60K Oxy (16 mg) HPC (16.8 mg) NA NA 0.05 0**0.07 301 NA NA 0.04** 0.37 MCC (160 mg) N60K Oxy (16 mg) PVP (9.3 mg) NANA 0.06 0.03 0.25 301 NA NA 0.11 0.26 APAP/Oxy 301 NA NA NA 0.78 1.30IR/GR Bilayer (both IR and GR have PVP as the binder)

Example 14

Studies were done to evaluate the effect of antioxidants on thedegradation rate of oxycodone in ER single layer tablets containing 500mg acetaminophen and 30 mg oxycodone HCl which were high sheargranulated with HPC as the binder. The antioxidant was added into thegranulation process based on the maximum allowance level from theInactive Ingredient Guide published by the FDA. The granules containingantioxidants were then blended with polyethylene oxide as described inprevious examples. Samples were then stored at 40° C., 75% relativehumidity (RH) in an open dish for 8 days, then analyzed. The results arepresented below in Table 48 and show that the antioxidants citric acid,sodium metabisulfite, cysteine HCl reduce the degradation of oxycodone,thus suggesting that introducing antioxidant into the granulationprocess may be beneficial in minimizing degradation of the oxycodone orany opioid present in the dosage form.

TABLE 48 DHOXY/OXY (%) t = 0 40° C., 75% RH, 8 days Antioxidant PolyoxRRT % RRT % Appearance none N60K 0.70 0.00 0.70 0.16 white to off- white301 0.70 NA 0.70 0.20 white to off- white BHT N60K 0.68 0.06 0.69 0.20white to off- white 0.72 0.05 301 0.70 NA 0.70 0.20 white to off- whiteAscorbic N60K 0.71 0.07 0.71 0.94 brown Acid 301 0.71 0.06 0.71 0.97brown Citric Acid N60K 0.72 0.05 0.72 0.04 slightly yellow 301 0.72 NA0.72 0.03 slightly yellow Sodium N60K 0.72 0.02 0.72 0.05 white to off-Metabisulfite white 301 0.72 0.06 0.72 0.04 white to off- white* SodiumN60K 0.70 NA 0.70 0.13 white to off- Sulfite white 0.72 0.03 0.72 0.04301 0.70 NA 0.70 0.20 white to off- white 0.72 0.04 0.72 NA Cystein HClN60K 0.68 NA 0.68 0.10 white to off- white 0.72 0.08 0.72 0.05 301 0.680.05 0.68 0.10 white to off- white 0.72 NA 0.72 0.05 *single yellow spatwas observed randomly on some of the tablets.

Example 15

To produce oral dosage forms in which the oxycodone exhibits enhancedstability against oxidative degradation, a high-shear fluid bedgranulation process was used in which the oxycodone HCl was granulatedin the presence of pregelatinized starch, citric acid, microcrystallinecellulose, and EDTA disodium salt, dehydrate.

Powdered oxycodone HCl, microcrystalline cellulose (MCC), and citricacid powder (an antioxidant) were mixed together and charged into ahigh-shear granulator. An aqueous solution containing pregelatinizedstarch (PGS) and Na₂EDTA was sprayed into the high-speed granulator,resulting in the formation of wet granules. The wet granules were thendried until less than about 2% water remained in the granules. The driedgranules had particle sizes ranging from about 100-300 μm. Thecomposition of the protected oxycodone granules is summarized in Table49.

TABLE 49 Dry Weight (% tot. Compound wt.) Oxycodone HCl 30.0% MCC 63.6%PGS 4.0% Na₂EDTA 0.4% Citric acid 2.0%

The protected oxycodone granules were divided into two groups to beincorporated into batches of instant release (IR) granules and intobatches of extended release (ER) granules used to form the IR and ERlayers of a bilayer tablet, respectively. Both the IR granules and theER granules were formed using separate fluid bed granulation processes.In each process, the previously-formed protected oxycodone granules,powdered acetaminophen (APAP), and various excipients includingdisintegrants, binders, and fillers were charged into the fluid bedgranulation device and sprayed with a granulation fluid, resulting inthe formation of IR granules in one batch and ER granules in a secondbatch. The composition of the resulting IR and ER granules aresummarized in Table 50.

TABLE 50 Dry Wt. (% total wt.) Compound IR Layer ER Layer Protectedoxycodone 16.1% 14.2% granules APAP 67.8% 81.2% MCC 5.0% Hydroxypropylcellulose 8.1% 4.5% Cross carmellose sodium 3.0%

The IR granules were blended with lubricant excipients in preparationfor the tablet pressing process. Similarly, the ER particles wereblended with various excipients including lubricants, and polyethyleneoxide polymer, and a filler in preparation for the tablet pressingprocess. The compositions of the IR blend and the ER blend aresummarized in Table 51 below.

TABLE 51 Dry Wt. (% total wt.) Compound IR Blend ER Blend IR granules99.25% GR granules 52.30% Silicon dioxide 0.50% 0.50% Magnesium stearate0.25% 0.10% MCC 1.20% Polyethylene oxide 45.00% polymer

The IR blend and the ER blend were loaded into a bilayer tablet pressand formed into bilayer tablets having about 29% of the IR blend andabout 71% the ER blend by weight.

A bilayer tablet was manufactured according to the method described inExample 15 according to the formulations in Table 52 (IR portion) andTable 53 (ER portion). The total tablet weight was 1006.5 mg.

TABLE 52 Ingredient mg/tablet wt % Acetaminophen 196.00 67.24 OxycodoneHCl 14.00 4.80 Avicel (within protected 29.67 10.18 granule) Spress B8251.87 0.64 Citric Acid Anhydrous 0.93 0.32% EDTA disodium salt, 0.17 0.06dihydrate Hydroxypropyl cellulose 23.32 8.00 AcDiSol 8.74 3.00 Avicel(as part of IR 14.57 5.00 granule) Silicon Dioxide 1.46 0.50 Mg Stearate0.73 0.25 Total 291.5 100.0

TABLE 53 Ingredient mg/tablet wt % Acetaminophen 304.00 42.52 OxycodoneHCl 16.00 2.24 Avicel (within protected 33.89 4.74 granule) Spress B8252.15 0.03 Citric Acid Anhydrous 1.07 0.15 EDTA disodium salt, 0.21 0.03dihydrate Hydroxypropyl cellulose 16.87 2.36 Polyox 321.75 45.00 Avicel(added to GR blend) 8.37 1.17 Silicon Dioxide 3.58 0.05 Mg Stearate 7.151.00 Total 715.0 100.0

In vitro release profiles may be determined for the formulated tabletdescribed above using standard USP Dissolution and Disintegrationapparatuses as described in Examples above. In vivo studies to determine

Example 16

Opioid agonists such as oxycodone have been reported to cause areduction in motility in the antrum, which results in slowing of gastricemptying (Wood and Galligan, Physicians' Desk Reference, 59^(th) edition(2005) p. 2818). This could affect the erosion time of an extendedrelease gastric retained acetaminophen/opioid combination drugformulation. Preliminary studies were done to determine the effect ofoxycodone on erosion time of acetaminophen extended-release tabletscomprising a polymer matrix that swells to a size sufficient forretention in the stomach in the fed mode.

This was a randomized 2-way crossover study in 5 healthy female beagledogs weighing between 12-16 kg to determine the erosion time ofacetaminophen gastric retentive extended-release tablets with andwithout oxycodone administration. Following an overnight fast of atleast 14 hours, the dogs were fed 100 g of canned dog food (Pedigree®Traditional ground Dinner with Chunky Chicken).

Fifteen minutes after the animals had consumed the food, the dosageforms were administered. In the oxycodone arm, oxycodone (14 mg in agelatin capsule (0.28 mL of a 50 mg/mL solution in water)) wasadministered with the tablet to simulate the immediate-release portionof the proposed formulations. This was followed by a simulatedextended-release over the next 4.5 hr (1.8 mg oxycodone in a gelatincapsule (0.036 mL of a 50 mg/mL solution in water) every 30 min for 4.5hr) for nine doses and a total of 16 mg oxycodone. In addition to theinitial feeding the animals were fed another 100 gm of food 4 hoursafter the first meal. The above procedure was repeated 2 day later withthe opposite treatment.

Erosion of the gastric retentive extended-release acetaminophen tabletswas assessed using fluoroscopy. Each tablet contained two radio-opaquestrings in the shape of an “X”. Separation of the strings was consideredto signify complete erosion of the tablets. Images were obtained every30 min until the strings separated. Individual and mean tablet erosiontimes are presented in Table 35. There was not a significant difference(p>0.05) in erosion time between control and oxycodone.

TABLE 54 Tablet Dog 1 Dog 2 Dog 3 Dog 4 Dog 5 Mean ± SD Control 4.25 h4.75 h 4.75 h 4.75 h 4.75 h 4.65 ± 0.22 h Oxy- 6.00 h 5.25 h 5.75 h 5.25h 4.75 h 5.40 ± 0.49 h codone

It was unexpectedly found that the co-administered oxycodone had nosignificant effect on the erosion time.

Example 17

A study to determine the erosion time of different extended releasegastric retentive dosage forms as described herein is done using dogs asa means to predict the drug delivery time in humans. The bilayer tabletscontaining both the extended release and immediate release componentsare used in these studies. Each tablet has a total weight of about 1000mg and contains 500 mg acetaminophen and 15 or 30 mg oxycodone HCl asindicated in Table 36. The gastric retentive (GR) portions of thetablets are formulated according to Example 2 above with the exceptionof the variations noted in Table 36. The immediate release (IR) layer isformulated according to Example 3 above, except that eitherhydroxypropyl cellulose or povidone is used as the binder as describedin Table 36.

TABLE 55 Oxycodone HCl Polymer (weight Formulation (mg/tablet) percent)Binder (weight percent) 1 15 POLYOX ® N60 K or GR: PVP, 3 to 15 weightpercent (6 hr release) 301 IR: PVP or HPC (hydroxypropyl cellulose)weight percent ranging 3 to 15 weight percent from 10 to 55% 2 15POLYOX ® N60 K or GR: PVP, 3 to 15 weight percent (8 hr release) 301 IR:PVP or HPC (hydroxypropyl cellulose) weight percent ranging 3 to 15weight percent from 15 to 55% 3 30 POLYOX ® GR: PVP, 3 to 15 weightpercent (6 hr release) N60 K or 301 IR: PVP or HPC (hydroxypropylcellulose) weight percent ranging 3 to 15 weight percent from 10 to 55%4 30 POLYOX ® N60 K or GR: PVP, 3 to 15 weight percent (8 hr release)301 IR: PVP or HPC (hydroxypropyl cellulose) weight percent ranging 3 to15 weight percent from 15 to 55%

A four-way crossover study is carried out in five healthy female beagledogs. Following an overnight fast of 14 hours, the dogs are fed 100 gcanned dog food. Fifteen minutes after the food has been consumed, thedogs are dosed with one of the four formulations to be tested. Fourhours after the initial meal, the animals are fed another 100 g ofcanned dog food.

Erosion of the gastric retentive extended releaseoxycodone/acetaminophen tablets is assessed using fluoroscopy. Eachtablet used in this protocol contains two radio-opaque strings in theshape of an “X.” Separation of the strings is considered to signifycomplete erosion of the tablets. Images are obtained every 30 minutesuntil the strings separate. The above procedure is repeated at 3-4 dayintervals until each dog has been administered four formulations.

Example 18

Erosion studies were carried out to test the erosion times of thetablets containing 500 mg acetaminophen and 15 mg oxycodone HCl asformulated in Tables 35-36 and 38-39 and tablets containing 500 mgacetaminophen and 30 mg oxycodone HCl as formulated in Tables 41-42 and44-45.

This study was conducted in 5 healthy female beagle dogs weighingbetween 12-16 kg to determine the erosion time of the bilayer tablets.Following an overnight fast of at least 14 hours, the dogs were fed 100g of canned dog food (Pedigree® Traditional Ground Dinner with ChunkyChicken). Within 15 minutes of the dog consuming the meal they wereadministered one of the acetaminophen/oxycodone bilayer tabletformulations. Each dog received each formulation with at least 3 daysbetween administrations. Erosion of the gastric retentiveextended-release acetaminophen/oxycodone tablets was assessed usingfluoroscopy. Each tablet contained two radio-opaque strings in the shapeof an “X.” Separation of the strings was considered to signify completeerosion of the tablets. Images were obtained every 30 minutes until thestrings separated. The erosion results and predicted human erosion times(delivery times) are listed in Table 56 below and illustrated in FIG.27.

TABLE 56 15/500 6 h tablet 15/500 8 hr tablet 30/500 6 hr tablet 30/5008 hr tablet Predicted Predicted Predicted Predicted Dog human Dog humanDog human Dog human erosion erosion erosion erosion erosion erosionerosion erosion Dog # time (h) time (h) time (h) time (h) time (h) time(h) time (h) time (h) 1 3.25 6.18 7.25 12.18 7.25 12.18 7.75 12.93 23.00 5.80 7.25 12.18 4.25  7.68 9.25 15.18 3 5.25 9.18 6.75 11.43 7.2512.18 8.25 13.68 4 4.75 8.43 6.25 10.68 7.75 12.93 8.75 14.42 5 3.756.93 4.75  8.43 6.75 11.43 7.25 12.18 Mean ± 4.00 ± 0.97 7.30 ± 1.456.45 ± 1.04 10.98 ± 1.56 6.65 ± 1.39 11.28 ± 2.08 8.25 ± 0.79 13.68 ±1.18 SD

No significant difference was observed between the in vitro erosiontimes for the 15 mg and 30 mg oxycodone formulation tablets. However, invivo erosion indicated that oxycodone may have an effect on erosion asthe 30 mg tablets had about a 2 hour increase in erosion time ascompared to the tablets containing 15 mg oxycodone. Tablets containing15 mg oxycodone did not appear to have a significant effect on erosionas erosion time for the tablet containing 15 mg oxycodone formulated for6 hour release was not different from that for the tablet containingacetaminophen only formulated for 6 hour release.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

It is claimed:
 1. A solid oral dosage form, comprising: an immediaterelease portion comprising a first dose of acetaminophen and a firstdose of opioid; an extended release portion comprising a second dose ofacetaminophen and a second dose of opioid thereof in a hydrophilicpolymer that swells upon imbibition of fluid to a size sufficient topromote gastric retention of the extended release portion in agastrointestinal tract of a subject, wherein said second doses of opioidand acetaminophen are released from the dosage form such thatsubstantially all of each of the second doses is released within aboutten hours, when measured in an in vitro disintegration test using a USPapparatus at 37° C. in 0.1N HCl; wherein upon oral administration of thedosage form to a subject, the opioid does not significantly affect theerosion time of the dosage form.
 2. The dosage form of claim 1, whereinthe first dose and the second dose of opioid comprise an opioid selectedfrom the group consisting of oxycodone or hydrocodone, orpharmaceutically acceptable salts thereof.
 3. The dosage form of claim1, wherein the sum of the doses of acetaminophen in the immediaterelease and extended release portions is about 325 mg.
 4. The dosageform of claim 1, wherein the opioid is oxycodone or a pharmaceuticallyacceptable salt thereof.
 5. The dosage form of claim 2, wherein the sumof the doses of oxycodone or a pharmaceutically acceptable salt thereofin the immediate release and extended release portions is about 7.5 mg.6. The dosage form of claim 1, wherein the opioid is hydrocodone or apharmaceutically acceptable salt thereof.
 7. The dosage form of claim 1,wherein the hydrophilic polymer is present in an amount ranging fromabout 35 wt % to about 50 wt % of the extended release portion.
 8. Thedosage form of claim 1, wherein the immediate release portion of thedosage form and the extended release portion of the dosage form comprisea bilayer tablet.
 9. A solid oral dosage form, comprising: an immediaterelease portion comprising a first dose of acetaminophen and a firstdose of opioid selected from the group consisting of oxycodone orhydrocodone, or pharmaceutically acceptable salts thereof; an extendedrelease portion comprising a second dose of acetaminophen and a seconddose of opioid selected from the group consisting of oxycodone orhydrocodone, or pharmaceutically acceptable salts thereof in ahydrophilic polymer that swells upon imbibition of fluid to a sizesufficient to promote gastric retention of the extended release portionin a gastrointestinal tract of a subject; wherein the acetaminophen andthe opioid are released during a period of gastric retention of betweenabout 4 hours to about 8 hours after oral administration; wherein dosesof acetaminophen are released from the dosage form such that about 40%to about 65% of the acetaminophen and about 20% to about 55% of theopioid are released from the dosage form within one hour, andsubstantially all of the acetaminophen and the opioid are released fromthe dosage form within about ten hours, when measured in an in vitrodisintegration test using a USP apparatus at 37° C. in 0.1N HCl; whereinthe sum of the doses of acetaminophen in the immediate release andextended release portions is about 325 mg, and the sum of the doses ofthe opioid in the immediate release and extended portions is about 7.5mg.
 10. The dosage form of claim 9, further comprising a chelatingagent, wherein the chelating agent is present in the extended releaseportion at an amount ranging from about 0.01 wt % to about 0.1 wt %. 11.The dosage form of claim 9, further comprising an antioxidant, whereinsaid antioxidant is present in the extended release portion at an amountranging from about 0.05 wt % to about 0.35 wt %.
 12. The dosage form ofclaim 11, wherein the antioxidant is citric acid.
 13. The dosage form ofclaim 9, wherein the hydrophilic polymer is present in the extendedrelease portion in an amount ranging from about 25 wt % to about 55 wt%.
 14. The dosage form of claim 13, wherein the hydrophilic polymer isselected from the group consisting of polyalkylene oxides, cellulosicpolymers, poly(acrylamides), poly(olefinic alcohols),poly(N-vinyl-lactams), polyvinylamines, polyvinylacetates andpolyimines.
 15. The dosage form of claim 9, wherein the polymer ispresent in the extended release portion in an amount ranging from about30 wt % to about 50 wt %.
 16. The dosage form of claim 9, furthercomprising a disintegrant in the immediate release portion.
 17. Thedosage form of claim 9, wherein upon oral administration of the dosageform to a subject the opioid does not significantly affect the erosiontime of the dosage form.